Inflammatory bowel disease (IBD) is a chronic disease with numerous remissions and relapses. A major challenge in the management of IBD is the prevention of relapse. Medical management of patients with acute exacerbation of IBD symptoms focuses on achieving remission by suppressing the aggressive immunological factors through down regulating the overactive immune system. The enhancement of protective aspects of the gastrointestinal mucosa is emerging as an important possible therapeutic approach that includes using scavengers of oxygen-derived free radicals. Appropriate medical management of remission often titrates the degree of drug-induced suppression to appoint just below the symptom threshold. Although the patient remains in clinical remission, activation of the immune system may produce a relapse by exceeding this threshold. A disruption in the balance between aggressive and protective factors must occur to cause reactivation of active disease. There are many aggressive factors in this disease and few natural protective factors.

Factors influencing IBD relapse:

1. Non-compliance to maintenance therapy.
2. Changes in smoking status.
3. Use of nonsteroidal anti-inflammatory (NSAIDs) agents.
4. Systemic and enteric infections.
5. Seasonal and environmental stimuli resulting in eosinophils activation.
6. 5 ASA (Mesalamine) sensitivity.

Noncompliance to maintenance therapy
In clinical practice 4-6 gms of 5 ASA or derivatives are required to induce remission. Half of these dosages are required generally to maintain remission. Most of the controlled trials do not give precise data for maintenance. Thus, some of the relapses may be due to inadequate maintenance dosing regimens based on this clinical teaching. First line therapy for mild to moderate acute ulcerative colitis is oral 5-ASA preparations or derivatives (4 g/day for 8 wk). Adjunctive topical 5-ASA (4-g enemas nocte or 500-mg suppositories b.i.d) has been shown to induce an earlier remission. Topical corticosteroids (hydrocortisone enemas 100 mg/day, hydrocortisone foams 80-160 mg/day) and oral glucocorticoids in doses that can be rapidly tapered (prednisone 40-60 mg/day tapered over 3 months) are administered to patients who do not respond. Long-term glucocorticoids will suppress symptoms but are not considered appropriate for maintenance regimens because of the side effects.

Numerous effective strategies that use topical rectal therapy to maintain remission have been studied, including low-dose enemas, alternate-day enemas, and one-week-a-month enemas. These agents are available as suppositories or enemas in the United States and as foams elsewhere. Anorectal and colonic physiology influences colonic distribution of oral or rectally administered drugs that require mucosal contact for therapeutic efficacy. The distribution of rectally administered mesalamine is related to the drug’s volume and viscosity. Colonic inflammation decreases luminal volume and enhances the spread of a fixed volume delivered to the rectum through enhanced sensitivity of the rectum to distension. If the luminal pressure or proximal colonic spasm is greater than internal anal sphincter relaxation induced by the volume distension of enema delivery, there is involuntary enema expulsion. Rectal contraction without enema loss forces the enema contents proximally into the sigmoid and descending colon. The volume and viscosity of suppositories diminish the distribution of the medication. Studies with mesalamine suppositories have shown distribution to about 20 cm.

Another principle of colonic physiology is often overlooked in developing a strategy for management. In the Colon proximal to the line of normal demarcation of disease, there is stasis of colonic contents. Oral drugs that work by topical mechanism are held in this part of the colon, limiting their distribution to the area of active inflammation. This observation may help explain the more rapid effect of topical rectal therapy.

The principles of distribution can help in the selection of drugs, depending on the location of the inflammation. The spread of 500-mg mesalamine suppositories is limited to 20 cm, treating the rectum, the rectosigmoid junction, and the distal sigmoid colon. Four-gram mesalamine enemas and 4-g foams have more proximal mucosal contact, with retrograde spreading in the sigmoid and descending colon. The extent of distribution of an enema is directly proportional to its volume. The contents of a 40-ml enema reach the splenic flexure in only 40% of patients, whereas a 60-ml enema reaches the splenic flexure reliably.

Because of these factors, the best medication contact time in the rectum and at the rectosigmoid junction can be obtained with suppositories. An understanding of this principle is useful in improving the retention of mesalamine or glucocorticoid enemas. The suppository’s distribution maximizes the effect of mesalamine on rectal inflammation.By controlling rectal inflammation, there is decreased rectosigmoid myoelectric activity and tenesmus, thus allowing accommodation of the enema.

Changes in smoking status
The epidemiological data support the concept that patients with ulcerative colitis are protected from the symptoms by smoking, while Crohn’s disease symptoms worsen by smoking. This status of tobacco use in relation to IBD has been interesting and perplexing. Nicotine might influence the enteric nervous system, altering the immune functions. Based on these findings nicotine patches are used to improve symptoms of ulcerative colitis. However, it is insufficient to provide a sustained remission.

Use of NSAIDs agents
Independent of established IBD, NSAIDs can induce colitis de novo. NSAIDs, have multiple gastrointestinal effects which activate colonic inflammation. Most interesting being altering intestinal permeability and activation of immune system by enhanced exposure to luminal contents. This can flare the existing IBD. NSAIDs also inhibit protective prostaglandin synthesis, inturn, again increasing intestinal permeability.

Systemic and Enteric Infections
It has been found interestingly that acute URTI can reactivate UC in children. URTI results in activation of immune system to eliminate viral infection. This also enhances the aggressive gastrointestinal mucosal immune system and thus leads to activation of ulcerative colitis.

Entric pathogens like Campylobacter jejuni, Salmonella, Shigella, Yersinia and E. coli have a strong association with relapse of IBD.

C. difficile infection has a controversial association with IBD. The clinician must differentiate C. difficile colitis and relapse of IBD on following useful points: 1) the diarrhoea is atypical for the usual flare of colitis, with watery, rather than bloody, mucoid diarrhoea; 2) C. difficile has a predilection for the caecum, causing right lower quadrant pain even in patients with left-sided UC; 3) C. difficile causes profound permeability changes, with rapid development of hypoalbuminaemia with a normal potassium value; and 4) the typical sigmoidoscopic appearance is an oedematous, hyperaemic mucosa, differing from the hyperaemic, granular mucosa characteristic of UC. Antibiotic treatment of a C. Difficile-related relapse with metronidazole or vancomycin should be followed by administration of a bile and acid-binding resin to bind the toxin while the normal colonic flora is being reestablished.

Seasonal and environmental stimuli resulting in eosinophils activation
In ulcerative colitis, eosinophils number increases during disease activity and declines in inactive disease. Recently eosinophil products have been found in increased concentration in lavage fluid from the gut during exacerbation of ulcerative colitis. These products are neurotoxins, substance P and vasoactive intestinal peptide (VIP).

Charcot-Leyden crystals in the stools of patients with active ulcerative colitis strongly suggest that tissue injury is eosinophil mediated. Such case require high-dose, short-term steroids to eliminate eosinophils and control the severity of relapse of ulcerative colitis.

5 ASA (Mesalamine) Sensitivity
It is known that oral or rectal sulphasalazine can reactivate colonic disease and may produce extraintestinal disease manifestation. Similar sensitivity has been observed with 5-ASA and olsalazine. There are distinctive clinical presentations of colonic mucosal 5 ASA sensitivity. Typically, the patient experiences a disease flare, which is treated by increasing the dose of mesalamine, with increasing symptoms. Corticosteroids are added to the regimen,and the symptoms remit. However, during the attempt to taper the corticosteroids, symptoms are reactivated. A key endoscopic sign of mesalamine toxicity is an oedematous and boggy mucosa with limited linear ulcerations. This is the appearance of “indeterminate colitis”, with the UC appearing to progress to Crohn’s disease. When the mesalamine is stopped, the symptoms generally improve within 72 h; however, the patient needs to be rechallenged cautiously to confirm sensitivity to mesalamine, which is the backbone of our treatment of ulcerative colitis.

In conclusion, because IBD relapse may be set off by many factors. Treating physicians should focus attention in each patient’s particular situation. Identification of the cause of relapse will direct to the optimal management of the patient’s disease.

Consultant Hepato-Gastroenterologist, Bombay Hospital Institute of Medical Sciences, Formerly Associate Prof. of Medicine and Gastroenterology at Grant Medical College and Sir JJ Group of Hospitals, Mumbai 400 008.