Glucocorticoid activity is dependent on specific glucocorticoid receptors (GR) found on chromosome 5. The GR-α isoform is a physiologically important form. GR-β does not bind glucocorticoids [9, 10], and GR-γ is a variant that may alter GR-α activity. Glucocorticoids bind to GR-α as a homodimer to specific glucocorticoid response elements (GREs) which activate gene expression. DNA binding of the GR, which activates gene expression, may be repressed by monomer protein-protein interactions that are also capable of DNA binding. This GRE pathway is crucial to survival [11]. Many glucocorticoid effects (e.g., anti-inflammatory and immunosuppressive) require the interaction of the GR with activating protein 1 (AP-1) and NF-κB transcription factors. These transcription factors are also capable of regressing GR-dependent transcription. The overall expected effect is GR-dependent transcription and activation of lymphocytes to result in apoptosis and anti-inflammatory effects [12].

High levels of the CXC-chemokines, growth-related oncogene (GRO)-α/CXCL1, IL-8, and gamma-interferon (MIG)/CXCL9 were detected in active ulcerative colitis when compared with controls (p = 0.02, 0.005, and 0.03, respectively). During treatment with corticosteroids, both GRO-α and MIG decreased [13]. HLA class II allele DRB1*0103 may be a “surrogate” marker for steroid resistance since it is associated with severe disease and high risk for colectomy.

Thirty percent of patients given glucocorticoids will not enter remission and are considered steroid resistant. Lymphocyte steroid resistance may be the key for glucocorticoid failure in UC [14], but this conclusion is hampered by varied lymphocyte sensitivity in normal subjects as well [15].

The impact of steroid resistance has been detailed in studies from the Mayo Clinic and Scandinavia. Faubion et al. [16] recorded a complete 30-day steroid-induced remission in 58 %, partial in 26 % (84 % total), and a failure in 16 %. One-year follow-up revealed 38 % of CD patients so treated required surgery as did 24 % of UC patients. Munkholm et al. [17] had reported a similar steroid-induced remission at 30 days (48 % complete, 38 % partial, total 80 %) and no response in 20 %. Interestingly, the failure of steroid responsiveness was not related to the severity of disease (i.e., remission rates of 48 % in severe versus 35 % in moderate disease) in the initial oral cortisone study [18].

There may be a rare familial disorder of altered glucocorticoid receptors resulting in mutations that encode GR [19–21]. These patients lack functional glucocorticoid receptors in target organs, yet counterintuitively these patients with poor glucocorticoid responses still suffer the ravages of glucocorticoid adverse events. Such glucocorticoid resistance appears unrelated to abnormalities in steroid absorption, metabolism, or number of glucocorticoid receptors. GR isoform variations may play a role, i.e., a greater preponderance of GR-β isoforms that do not bind glucocorticoids have been found in steroid-resistant UC patients [22]. The actual concentration of GR-β is small compared to GR-α [23]. GR-γ may affect glucocorticoid binding as an alternative theory of glucocorticoid resistance [24, 25]. Other thoughts on glucocorticoid resistance include impaired binding or a reduced number of receptors available for binding of DNA resulting in a GR-ligand complex failure to activate the appropriate genes [26].

Glucocorticoids modulate transcription factors and cytokines. IL-4/IL-2 promotes steroid resistance in vitro [27] and in murine cell lines [28]. IL-2 reduces nuclear translocation of GR by adding a Janus kinase (JAK) inhibitor. JAK inhibitors block IL-2 receptor signaling and restore responsiveness to glucocorticoids. STAT5 is associated with nuclear GR and when phosphorylated by IL-2 binding will inhibit nuclear translocations of GR. In a STAT5 knockout mouse model, IL-2 fails to induce steroid resistance [27]. IL-2 and IL-4 cytokines increase p38 mitogen-activated protein (MAP) kinase which phosphorylates GRs associated with steroid resistance [29] and reduces antiproliferative glucocorticoid activity [27]. Steroid-resistant patients usually produce more IL-2 than steroid-sensitive patients.

NF-κB regulates cytokine synthesis with a peculiar epithelial cell distribution in steroid-resistant patients, yet this is also found in lamina propria macrophages in steroid-sensitive patients [30]. The conclusion seems inescapable that lymphocyte resistance to glucocorticoids results from signaling pathways activated by IL-2. Conceivably inhibiting IL-2 overcomes this resistance. Unfortunately, in vitro-activated lymphocyte studies show a surprisingly low IL-2 production which was not correlated with steroid sensitivity.

Membrane cytokine binding activates transcription factor in the receptor complex and produces inflammation. Glucocorticoids oppose this process by promoting apoptosis to lessen inflammation [31].

Genetic factors add to the glucocorticoid receptor disorders with steroid resistance. These include the multidrug resistance 1(MDR1) gene. The MDR1 gene product, a P-glycoprotein 170 found in colonic and jejunal tissue [32], transports glucocorticoids and reduces intracellular fluid drug and glucocorticoid concentrations. High levels of P-glycoprotein 170 are protective in UC but may be downregulated by inflammation [33]. It is uncertain if MDR1 polymorphisms are related to steroid resistance (Table 10.2).

The actual benefit of glucocorticoids in controlling diarrhea in IBD may also include the significant stimulation of ATPase activity and the number of ATPase molecules and apical 5′-nucleotidase, all of which precede the observable morphologic effect on inflammation as detected by endoscopy or histology [34, 35].

Rectal potential differences (PDs) as a measure of ion transport across the rectal mucosa improved after glucocorticoids (both topical and systemic therapy) as well as with 5-ASA enemas. The clinical utility and significance of this observation remains unexplored [36].

Glucocorticoid receptors are present in most human cells. This widespread receptor presence may well explain the systemic glucocorticoids adverse event history [37]. Rectal glucocorticoids are presumed to provide lesser systemic bioavailability and plasma concentration than oral glucocorticoids. Nevertheless plasma concentrations of prednisolone given rectally have been reported as equivalent to orally administered glucocorticoids [37, 38].

The bioavailability is further reduced with foam preparations (2 %) with even lower plasma peak levels (Table 10.3) [39].

Although decreased glucocorticoid receptor sites are reported in PMN leukocytes of prior steroid-treated patients, similar reduced receptor sites have been reported in glucocorticoid-naïve and normal control patients [40]. Topical glucocorticoids are effective, but systemic absorption does occur [41] but may be lessened with rapidly metabolized budesonide. These were effective with maintenance of normal ACTH levels in 90 % of patients at 6 weeks [42].

In 1997, Marshall and Irvine reported a meta-analysis of 33 reviewed rectal corticosteroids studies that met their “strict” inclusion criteria of 83 published reports [43]. Inclusion criteria required randomization, disease distal to splenic flexure, a predefined symptom score, and no inclusion of Crohn’s patients or duplicate reporting of trial data. The response rates based on symptomatic, endoscopic, and histological criteria for conventional oral glucocorticoids (hydrocortisone, prednisolone, or betamethasone) were 77, 66, and 58 % with remission rates of 45, 34, and 29 %. The response to topical corticosteroids (budesonide, BDP, or prednisolone) was 73, 69, and 55 % with remission rates of 46, 31, and 23 %.

In this analysis, 5-ASA preparations resulted in improvement in 81, 75, and 65 % with remission recorded as 58, 41, and 38 %. Placebo response rates were 34 % symptom and 38 % endoscopic improvement, and remission rates of symptomatic and endoscopic criteria of 9 and 17 %.

Although topical corticosteroids were 32 % superior to placebo, seven trials proved 5-ASA to be superior to corticosteroids when considering clinical, endoscopic, and histological standard of remission. The result of pooled odds ratio (2.42 95 % CI 1.7–3.41) favored 5-ASA for symptomatic remission, as well as endoscopic (1.89 95 % CI 1.26–2.96) and histological (2.03 95 % CI 1.28–3.2) remission. This occurred even with discrepant volumes of instilled medication (e.g., 30 cc prednisolone foam versus 120 cc 5-ASA foam) [44]. Furthermore a Cochrane analysis of 38 studies reaffirmed rectal 5-ASA superiority over rectal corticosteroids for inducing symptomatic improvement and remission [45].

Throughout all these analyses, a placebo benefit of 30 % and a remission placebo rate of 10 % must be kept in mind when evaluating efficacy [46]. Foam and suppositories will provide a higher response rate in distal UC [42] and better patient compliance [47]. As anticipated, higher endoscopic and histological remission rates accrued with longer treatment duration [44, 48–61] and with lower relapse rates [62, 63].

The Marshall and Irvine meta-analysis concluded that rectal 5-ASA is comparable to rectal glucocorticoids for improvement, but better for inducing remission. This was consistent across symptomatic, endoscopic, and histological outcomes. However, 5-ASA was as effective as budesonide in two trials regarding improvement and remission but failed to meet all end points. Adverse events were comparable for all rectal preparations of budesonide albeit with less endogenous cortisol suppression than conventional glucocorticoids based on serum cortisol determinations.

The role of rectal corticosteroids is an alternative distal colitis treatment in patients failing or intolerant to 5-ASA preparations. 5-ASA preparations were superior to glucocorticoids in active disease as well as maintenance of remission (Table 10.4).

In 2000, Cohen et al. [64] visited therapy for left-sided UC and proctitis via a meta-analysis of the accumulated literature through 1997 and concluded that topical 5-ASA again was superior to oral therapies or topical glucocorticoids. In left-sided disease, 5-ASA’s higher remission rate over glucocorticoid enemas was not dose dependent. Similarly 5-ASA suppositories were superior to glucocorticoid topical therapy in ulcerative proctitis, but no dose response could be established. Overall, the authors concluded remission and improvement rates of 10–80 % with 5-ASA enemas over oral 5-ASA and glucocorticoid enemas.

Confounding features of meta-analyses open to criticism include different study populations, methodologies, and variation in study design. Odds ratios can be exaggerated by 17 % if studies are not double blinded [65], 30 % if lacking randomization [66], 41 % if inadequate concealment of treatment allocation, or 30 % if unclear concealment [65].

In a detailed analytic review of therapeutic trials for left-sided ulcerative proctitis, Regueiro et al. in 2006 evaluated the literature from 1995 through September 2005 [67]. Their assessment required multiple high-quality, randomized, controlled trials with consistent results to merit “A+” grade down to “D” for expert opinion only. Trials were excellent only if specifically designed for left-sided disease, with positive results compared to placebo or a comparative drug.

Rectally administered corticosteroids rated A+ on evidence and excellent efficacy with a clear advantage of 4–5 times more likely to have symptomatic and endoscopic improvement than placebo. Pooled OR was 0.21 (95 % CI 0.07–0.71) for symptom and 0.27 (95 % CI 0.10–0.77) for endoscopic improvement [68].

Rectal glucocorticoids for maintenance of remission fare poorly and should be considered ineffective for this indication; in addition, there are the added adverse effects that it carries (osteoporosis, cataracts, avascular necrosis, etc.). Indeed there was no value or gain of oral glucocorticoids over placebo after 6 months (as noted in the earliest study in 1965) [69]. The oral steroid therapy data from the Mayo Clinic are clearly unfavorable for any sustained benefit, i.e., the 1-month combined partial and complete remission note of 84 % diminished to 49 % without glucocorticoids at 1 year, 22 % of patients became dependent on glucocorticoids, and 29 % required colectomy [16].

No benefit was noted with a maintenance dose of rectal hydrocortisone 100 mg biweekly for 6 months [70]. No rectal budesonide (2 mg biweekly) maintenance benefit versus placebo could be established [71].

Proctitis may become a vexing problem when active. 5-ASA or glucocorticoid suppositories given 2–3 times daily may be helpful even with the expected difficulty of retaining them with refractory disease [67].

5-ASA or glucocorticoid enemas and glucocorticoid foam have been the mainstays of topical therapy for rectosigmoid UC. Occasionally enema preparations may skip (or bypass) the inflamed irritable rectal sigmoid due to instillation with the patient on his or her left side. Suppositories are recommended 2–3 times daily as supplemental rectal medication until relief is achieved [71].

Using this first-pass metabolized steroid, beclomethasone dipropionate (BDP), in 177 UC patients, the clinical remission rate was virtually identical (63 %) to that achieved by 5-ASA (62.5 %). Although a more favorable improvement in disease activity indices occurred in patients with more extensive disease with BDP, the plasma cortisol levels were significantly reduced in the BDP group. This was not a placebo-controlled trial [112]. BDP was found to be as effective as 5-ASA by inducing improvement on remission in 70 % (148 patients) of patients versus 65.3 % (143 patients) given 5-ASA, when given topically (foam/enema) in 488 patients culled from four clinical trials. BDP’s high first-pass hepatic elimination provides significantly less systemic bioavailability with reduced GCS side effects while maintaining efficacy [113]. Mild-to-moderately active UC patients did best with oral beclomethasone dipropionate but less so was achieved in proctitis patients. Of the 394 UC patients not in remission, when given oral 5-ASA, rectal 5-ASA, or rectal steroids, 81.7, 39.8, or 9.4 %, respectively, occurred with remission; BDP at 5 or 10 mg/day resulted in remission in 44.4 %, response in 22.3 %, and failure in 33.7 %. Adverse events included headache and nausea in 7.6 %. 6.6 % required hospitalization and 1 % went to colectomy [114].

BDP’s safety was evaluated in 8 UC patients using the 1 mg ACTH test of the pituitary-adrenal axis reserve. Fasting and peak cortisol responses to ACTH were suppressed in 6/8 patients. One patient with suppressed fasting cortisol and another with a “blunted” ACTH response were noted as well 2 weeks after initiation of BDP therapy. One month after cessation of BDP, 7/8 patients’ ACTH tests were normal. Comment: BDP in an enema formulation is capable of significant suppression of the pituitary-adrenal axis [115].