Sulfasalazine (Salazosulfapyridine, SASP) is a prodrug composed of a molecule of 5-aminosalicylic acid (5-ASA) and sulfapyridine , linked by an azo bond. It was aimed to the treatment of rheumatic diseases such as rheumatoid arthritis and ankylosing spondylitis. When taken orally, anaerobic intestinal bacteria split the azo bond, releasing the two components 5-ASA and sulfapyridine, the former being the active anti-inflammatory component [1]. Because the lower G-I tract—terminal ileum and colon—are the areas of the gut with the highest commensal bacteria concentration (10¹⁰–10¹⁴ cfu/mm³), it was assumed that the 5-ASA moiety would exert its anti-inflammatory activity in the inflamed and ulcerated areas of the intestine where the active compound would be released [2, 3].

The mechanism of action of SASP and its metabolites is not well understood [4], especially their systemic effect on rheumatic diseases, since 5-ASA is poorly absorbed into the bloodstream [3]. The fact that the active molecule is particularly effective when administered topically into the rectum, as enema or suppository, supports this concept. It has been reported that SASP and its metabolites decrease eicosanoid synthesis [5–7], cytokine expression [8–10], and NF-kB activation [11, 12].

The antioxidant effects of SASP are well established which are probably due to its scavenging effects against reactive oxygen and nitrogen species (ROS and RNS), as well as metal chelating properties, and its inhibitory effects over neutrophil oxidative burst [13, 14]. A study compared the potential scavenging activity mediated by SASP and its metabolites 5-ASA and sulfapyridine on ROS and RNS, using validated in vitro screening systems [15]. SASP and its metabolite 5-ASA, but not sulfapyridine showed ROS- and RNS-scavenging effects which may be a contributing mechanism of its anti-inflammatory effects through the prevention of the oxidative/nitrative/nitrosative damages caused by these species [15].

As mentioned, the fact that the effect of anaerobic bacteria is necessary to “activate” SASP explains why it has been used in ulcerative colitis where it has been shown to be effective in both inducing remission of active disease and preventing relapse in inactive patients. However, the role of SASP in the treatment of mild or moderate Crohn’s disease is controversial still nowadays [16].

SASP was used in the treatment of active Crohn’s disease on the belief that it would benefit of a treatment that has been effective in active ulcerative colitis, provided the similarity of mucosal lesions between both diseases. On the other hand, in the early sixties there were no other drugs available for such conditions, except for corticosteroids. Since Crohn’s disease may affect independently the colon, the terminal ileum or both together, and both areas contain a high anaerobic bacteria concentration , it is logical to assume that the prodrug could be split by them in both locations and locally release 5-ASA. Some observational studies were published in the sixties and early seventies of the last century [17–19] to assess the effectiveness of SASP for both inducing and maintaining remission in Crohn’s disease. Also in this decade, controlled trials were also performed with different designs to ascertain its effect as adjunctive therapy in active disease or as maintenance treatment, most of them with a small and heterogeneous group of patients [20, 21].

The first solid evaluation of the effect of SASP on Crohn’s disease comes from two large studies: the American National Cooperative Crohn’s Disease Study (NCCDS) [22] and the European Cooperative Crohn’s Disease Study (ECCDS) [23].

The NCCDS compared the efficacy of SASP, prednisone and azathioprine with placebo, and showed that prednisone (0.25–0.75 mg/kg adjusted to disease activity) was superior to SASP (1 g/15 kg), and that SASP, but not azathioprine (2.5 mg/kg), was superior to placebo, in inducing 16-week clinical remission of Crohn’s disease [22]. Subgroup analyses suggested that patients who had been treated with steroids previously failed to respond to SASP, while those who had not taken steroids at entry responded to SASP significantly better than placebo [22]. Patients with involvement limited to the colon responded to SASP better than to placebo, while those who had disease located only in small bowel were less likely to benefit from this therapy [22]. None of the treatments—including SASP—proved to be better than placebo for preventing clinical relapse in inactive disease [22].

The ECCDS randomized patients to treatment with 6-methylprednisolone (48 mg/day weekly, tapering to 8 mg/day) alone, 6-methylprednisolone in combination with SASP (3 g), SASP alone, or placebo. Effects on active disease where assessed at 6 weeks, whereas inactive patients were on therapy for 2 years or until relapse. 6-Methylprednisolone proved the most effective therapy for inducing remission [23]; in subgroup analyses it was significantly more effective than SASP for patients who had been previously treated with steroids , for those who had disease only in the small bowel, and for those with disease in the small bowel and colon [23]. The combination of the steroids plus SASP was most effective in previously untreated patients and when the disease was located in the colon [23]. SASP alone was the least effective active treatment regimen. No therapeutic regimen was better than placebo for inactive disease [23].

Other controlled trials in patients with active Crohn’s disease have confirmed some of the conclusions of these subgroup analyses by demonstrating that SASP is not an effective adjunctive therapy to prednisone [21], whereas prednisolone is an effective adjunctive therapy to SASP [24], probably because corticosteroids are more effective therapies than SASP. In another small, comparative study of SASP (4–6 g/day) with placebo, van Hees et al. showed that 62 % of patients treated with SASP had a favorable response after 26 weeks compared with 8 % of placebo-treated patients [25].

In 2010, meta-analysis pooled the available data on the effect of different salicylates in mild-to-moderate active Crohn’s disease [26]. SASP was more likely to induce remission (RR: 1.38; 95 % CI: 1.02–1.87; n = 263) compared to placebo, with benefit confined mainly to patients with colitis, while it was less effective than corticosteroids (RR: 0.66; 95 % CI: 0.53–0.81; n = 260) [26]. Interestingly, however, the performance of SASP was better than that of mesalazine , either at low or high dose. Low-dose mesalazine (1–2 g/day) was not superior to placebo (RR: 1.46, 95 % CI: 0.89–2.40; n = 302) and was less effective than corticosteroids. High-dose mesalazine (3–4.5 g/day) was not superior to placebo for induction of remission (RR: 2.02; 95 %: CI 0.75–5.45) or response (Weighted mean difference: −19.8 points; 95 % CI: −46.2 to 6.7; n = 615). The authors conclude that SASP shows modest efficacy for the treatment of active Crohn’s disease [26]. In a more recent meta-analysis, Ford et al. [27] just showed a trend towards a benefit with sulfasalazine over placebo (two RCTs, RR of failure to achieve remission = 0.83; 95 % CI = 0.69–1.00), and also no definite benefit of mesalazine over placebo (four RCTs, RR = 0.91; 95 % CI = 0.77–1.06). Neither sulfasalazine nor mesalazine was effective in preventing quiescent CD relapse [27] However, a direct comparison between SASP and mesalazine in mild-to-moderate active Crohn’s disease has never been performed.

Another setting where aminosalicylates have been assayed is the prevention of postoperative recurrence of Crohn’s disease after resection and ileo-colonic anastomosis. A meta-analysis has pooled the data of 11 trials, five of them using SASP [20, 28–31], with a total of 1282 patients [32]. The RR of relapse of Crohn’s disease in remission after surgery with aminosalicylates vs. placebo or no therapy was 0.86 (95 % CI: 0.74–0.99) (NNT = 13). As opposite to treatment of active disease, SASP was of no benefit in preventing relapse (RR: 0.97; 95 % CI: 0.72–1.31; n = 448), whereas mesalazine was more effective than placebo or no therapy (RR: 0.80; 95 % CI: 0.70–0.92; n = 834), with a NNT = 10 [32]. The authors conclude that mesalazine has only a modest effect in preventing postoperative recurrence in Crohn’s disease and should be used in patients in whom immunosuppressive therapy is either not warranted or contraindicated [32].

On the light of the available evidence, both experts [33, 34] and consensus-based guidelines [16] recommend the use of high-dose (3–6 g/day) SASP in Crohn’s disease only for patients with mild disease confined to the colon. Other authors, however, do not give any chance to SASP and its metabolites in the management of active Crohn’s disease [35]. Anyway, SASP should be used in the short term, and active disease beyond 16 weeks of therapy should be considered a therapeutic failure. In addition, SASP are ineffective as maintenance therapy after both medically and surgically induced remission (in the latter setting, mesalazine may have a minor role).

In addition, SASP may have a role in the management of Crohn’s disease patients with associated arthropathy. However, recent review of the available evidence indicates that its usefulness is confined to some patients with peripheral arthropathy, or in those with early ankylosing spondylitis (i.e., those with higher levels of ESR or active disease) [36]. Advanced disease does not benefit from this drug since no effect on physical function, pain, spinal mobility, or enthesitis has been observed [36].