Introduction
Peptic ulcers comprise gastric and duodenal ulcers.
Complications of peptic ulcers include bleeding, perforation and
obstruction (1). Bleeding is a major
problem of peptic ulcers, as it is at times fatal (2). Peptic ulcer bleeding is diagnosed and
treated by upper gastrointestinal (GI) endoscopy (3). Known causes of peptic ulcer bleeding
are the long-term administration of non-steroidal anti-inflammatory
drugs (NSAIDs), anti-platelet agents, anti-coagulants and infection
with Helicobacter pylori (4).
NSAIDs are commonly used for rheumatic diseases and
persistent pain due to orthopedic diseases (5,6).
Rheumatic diseases have an autoimmune basis and affect connective
tissue (6,7). This inflammation damages tissue and
impairs the patient's quality of life (8,9). To
suppress the autoimmune basis of the disease, corticosteroids and
immunosuppressive agents are used (10–12).
Tumor necrosis factor a blockers, biological modifiers, are also
used to suppress the autoimmune response (13,14). It
is well known that corticosteroids trigger peptic ulcer bleeding by
making the gastric mucosa susceptible to ulceration by gastric acid
(15–17). However, the correlation between
immunosuppressive agents and upper GI bleeding has remained to be
determined.
For the prevention of peptic ulcer bleeding, proton
pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs)
are used (18). PPIs and H2RAs
increase the pH of gastric acid, prevent damage of the gastric
mucosa and promote the healing of peptic ulcers (19,20).
PPIs are superior to H2RAs in preventing peptic ulcer bleeding due
to stress in patients in intensive care (21). However, the efficacy of the
prevention of peptic ulcer bleeding has remained elusive in
patients with long-term administration of PPIs or H2RAs.
In the present study, the association between peptic
ulcer bleeding and administration of NSAIDs, corticosteroids and
immunosuppressive agents was analyzed in patients with rheumatic or
orthopedic diseases. Furthermore, the prevention of peptic ulcer
bleeding by PPIs and H2RAs was evaluated.
Materials and methods
Ethics statement
The present study was approved by the National
Hospital Organization Shimoshizu Hospital Ethics Committee
(Yotsukaido, Japan). It was not considered a clinical trial, as the
procedures were performed as part of a routine clinical practice.
Written informed consent for inclusion in the study was waived.
Patient records were anonymized and retrospectively analyzed.
Written informed consent was obtained from all patients who were
subjected to upper GI endoscopy.
Patients
Medical records were retrospectively analyzed for
patients subjected to upper GI endoscopy performed at the National
Hospital Organization Shimoshizu Hospital (Yotsukaido, Japan) from
October 2014 to September 2015. During this period, a total of
1,023 patients underwent an upper GI endoscopy for the
investigation of anemia, abdominal pain or tarry stool. In
addition, certain patients underwent upper GI endoscopy for
screening. The cohort comprised 431 males (age, 68.1±12.9 years)
and 592 females (age, 66.4±12.3 years).
Study design
The 1,023 patents were analyzed with regard to
administration of NSAIDs, corticosteroids, immunosuppressive
agents, PPIs and H2RAs. Endoscopic findings were reviewed in the
1,023 patients; these data were analyzed statistically. For
patients with bleeding from peptic ulcers, results of urea breath
test and past history of peptic ulcers were reviewed. The urea
breath test was performed to detect Helicobacter pylori infection
and outsourced to LSI Medience Corp. (Tokyo, Japan).
Medication
The cohort of the present study had received
immunosuppressive agents, including methotrexate and tacrolimus, as
well as biological agents, including infliximab, etanercept,
adalimumab and golimumab. Corticosteroids and immunosuppressive
agents were used for rheumatic diseases, such as rheumatoid
arthritis and systemic lupus erythematosus. NSAIDs were
administered to patients with lumbar discopathy and deformation
spondylosis. Table I shows the
number and ratio of patients administered each type of drug.
 | Table I.Number of patients taking each
medication. |
Table I.
Number of patients taking each
medication.
| Medication | Number of
patients | Ratio, % |
|---|
| NSAIDs | 19 | 1.85 |
| Corticosteroids | 92 | 8.99 |
| Immunosuppressive
agents | 30 | 2.93 |
| PPI | 118 | 10.51 |
| H2RA | 30 | 2.93 |
Upper GI endoscopy
Patients were subjected to upper GI endoscopy for
screening, or investigation of abdominal symptoms or anemia. The
endoscopic devices used were the GIF-N260H, GIF-XP260NS, GIF-PG260,
GIF-XQ260 and GIF-Q260 (Olympus, Tokyo, Japan). A gastric or
duodenal ulcer was considered to be a peptic ulcer. Bleeding from a
peptic ulcer was restricted to a spurting vessel, an oozing vessel,
a visible vessel or a clot, according to the Forrest classification
system (22). Table II shows the diagnosis of patients
with peptic ulcer bleeding. Seventeen and two patients were
diagnosed with bleeding from gastric and duodenal ulcers,
respectively.
| Table II.Diagnosis of upper gastrointestinal
bleeding from peptic ulcers by endoscopy. |
Table II.
Diagnosis of upper gastrointestinal
bleeding from peptic ulcers by endoscopy.
| Peptic ulcer or
non-peptic ulcer | Diagnosis | Number of
patients |
|---|
| Peptic ulcer | Gastric ulcer | 17 |
|
| Duodenal ulcer | 2 |
| Total |
| 19 |
Statistical analysis
Logistic regression analysis was used to determine
the odds ratio and 95% confidence interval of peptic ulcer bleeding
for each medication. The Wald test was applied to analyze the
statistical significance of the correlation of peptic ulcer
bleeding and medication (23).
Chi-square tests were applied to analyze the correlation between
peptic ulcer bleeding and administration of PPIs or H2RAs.
P<0.05 was considered to indicate a statistically significant
difference. JMP 10.0.2 software (SAS Institute, Cary, CA, USA) was
used for statistical analysis.
Results
Patient characteristics
Table III shows the
characteristics of patients with bleeding from peptic ulcers. The
patients had been subjected to monotreatment with NSAIDs,
immunosuppressive agents or corticosteroid, but not their
combination. Four patients were subjected to the urea breath test,
one of which was positive and had a history of peptic ulcer.
| Table III.Characteristics of patients with
bleeding from peptic ulcers. |
Table III.
Characteristics of patients with
bleeding from peptic ulcers.
| Patient no. | Diagnosis | Gender | Age | Disease | NSAIDs | Immunosuppressive
agents |
Corticosteroids | History of peptic
ulcers | H.
pylori |
|---|
| 1 | GU | F | 79 | Lumbar
discopathy | (+) | (−) | (−) | (−) | NA |
| 2 | GU | M | 73 | RA | (−) | (−) | (+) | (−) | NA |
| 3 | GU | M | 73 | RA | (−) | (−) | (+) | (−) | NA |
| 4 | GU | M | 73 | RA | (−) | (−) | (+) | (−) | NA |
| 5 | GU | F | 66 | (−) | (−) | (+) | (−) | (−) | NA |
| 6 | GU | F | 67 | RA | (−) | (+) | (−) | (−) | NA |
| 7 | GU | M | 22 | DMD | (−) | (−) | (−) | (−) | NA |
| 8 | GU | M | 78 | (−) | (−) | (−) | (−) | (−) | NA |
| 9 | GU | M | 72 | (−) | (−) | (−) | (−) | (+) | NA |
| 10 | GU | M | 72 | (−) | (−) | (−) | (−) | (+) | NA |
| 11 | GU | M | 84 | (−) | (−) | (−) | (−) | (−) | NA |
| 12 | GU | M | 71 | (−) | (−) | (−) | (−) | (−) | NA |
| 13 | GU | F | 70 | (−) | (−) | (−) | (−) | (−) | NA |
| 14 | GU | M | 69 | (−) | (−) | (−) | (−) | (+) | (+) |
| 15 | GU | F | 84 | (−) | (−) | (−) | (−) | (−) | NA |
| 16 | GU | F | 87 | (−) | (−) | (−) | (−) | (−) | NA |
| 17 | GU | F | 70 | (−) | (−) | (−) | (−) | (−) | (+) |
| 18 | DG | F | 42 | (−) | (−) | (−) | (−) | (−) | (−) |
| 19 | DG | F | 42 | (−) | (−) | (−) | (−) | (−) | (−) |
Effect of the medication with regard
to bleeding
To calculate the odds ratios for various medication
types with regard to peptic ulcer bleeding, logistic regression
analysis was used (Table IV). The
odds ratio of immunosuppressive agents was 5.83, which was larger
than that of NSAID (4.77). It was found that among the different
medications, immunosuppressive agents had the strongest correlation
with peptic ulcer bleeding.
| Table IV.Logistic regression analysis of the
relationship between medication and bleeding from peptic
ulcers. |
Table IV.
Logistic regression analysis of the
relationship between medication and bleeding from peptic
ulcers.
| Medication | Odds ratio | 95% CI |
|---|
| NSAIDs | 4.77 | 0.25–26.25 |
|
Corticosteroids | 2.77 | 0.62–9.62 |
| Immunosuppressive
agents | 5.83 | 0.88–22.88 |
Confirmation of the association
between medication and bleeding
To confirm the association between immunosuppressive
agents and peptic ulcer bleeding, the Wald test was applied
(Table V). Immunosuppressive agents
had the largest χ2 result (4.98) and P=0.03 (Table V).
| Table V.Wald test of the association between
medication and bleeding from peptic ulcers. |
Table V.
Wald test of the association between
medication and bleeding from peptic ulcers.
| Medication | χ2 | P-value |
|---|
| NSAIDs | 2.12 | 0.15 |
|
Corticosteroids | 2.37 | 0.12 |
| Immunosuppressive
agents | 4.98 | 0.03 |
Proton-pump inhibitor and
bleeding
To reveal the correlation between PPIs and peptic
ulcer bleeding, a χ2 test was applied (Table VI). Administration of PPIs was
significantly correlated with non-peptic ulcer bleeding
(P=0.02).
| Table VI.Correlation between PPI intake and
bleeding from peptic ulcers. |
Table VI.
Correlation between PPI intake and
bleeding from peptic ulcers.
|
| Peptic ulcer
bleeding (P=0.02) |
|
|---|
|
|
|
|
|---|
| PPI intake | Negative, n
(%) | Positive, n
(%) | Total |
|---|
| Yes | 892 (87.19) | 13 (1.27) | 905 (88.47%) |
| No | 112 (10.95) | 6 (0.59) | 118 (11.53%) |
| Total | 1,004 (98.14) | 19 (1.86) | 1,023 (100%) |
Histamine type 2 receptor antagonist
and bleeding
To analyze the correlation between H2RAs and peptic
ulcer bleeding, a χ2 test was applied (Table VII). A tendency toward non-peptic
ulcer bleeding with administration of H2Ras was identified;
however, it was not statistically significant (P=0.12).
| Table VII.Correlation between H2RA intake and
bleeding from peptic ulcers. |
Table VII.
Correlation between H2RA intake and
bleeding from peptic ulcers.
|
| Peptic ulcer
bleeding (P=0.12) |
|
|---|
|
|
|
|
|---|
| H2RA intake | Negative, n
(%) | Positive, n
(%) | Total |
|---|
| Yes | 976 (95.41) | 17 (1.66) | 993 (97.07%) |
| No | 28 (2.73) | 2 (0.2) | 30 (2.93%) |
| Total | 1004 (98.14) | 19 (1.86) | 1023 (100%) |
Discussion
Case reports and case series have documented the use
of immunosuppressive agents to treat patients with peptic ulcers
(24–26). However, studies assessing the
possible association between the administration of
immunosuppressive agents and peptic ulcer bleeding are currently
lacking. To answer this question, the present case findings
provided novel evidence that immunosuppressive agent use is
significantly correlated with peptic ulcer bleeding. Although the
mechanisms by which immunosuppressive agent use may be correlated
with peptic ulcer bleeding is elusive, it is possible that these
agents cause bleeding by inhibiting ulcer healing (26). The results of the present study are
clinically important, as they are relevant to ensuring patient
safety, with peptic ulcer bleeding being one reason for the
discontinuation of immunosuppressive agents (27). Further studies with additional
patients are therefore warranted to confirm these results.
NSAIDs and corticosteroids cause gastric and
duodenal ulcers, and increase the risk of upper GI bleeding. In
previous studies, NSAIDs and corticosteroids were rated to not pose
any risk for peptic ulcer bleeding (28,29). In
the present study, NSAIDs and corticosteroids showed no correlation
with upper GI bleeding. The results of the present study are
therefore consistent with those of previous ones. However, it is
premature to conclude that NSAIDs and corticosteroids are less
hazardous. One reason is that in the present study, the number of
patients treated with NSAIDs and corticosteroids was relatively
small. Peptic ulcer bleeding is still fatal in certain patients,
such as the elderly (30).
Precautions should be taken for patients treated with NSAIDs and/or
corticosteroids to avoid upper GI bleeding.
PPIs are effective for reducing peptic ulcer
bleeding (31). They are more
effective at lowering the risk of upper GI peptic ulcer bleeding
than H2RAs (32). In the present
study, PPIs significantly lowered the risk of peptic ulcer
bleeding. Therefore, the results of the present study were
consistent with those of previous ones. PPIs are frequently used in
combination with NSAIDs or corticosteroids to lower the risk of
peptic ulcer bleeding (10,33). Likewise, PPIs may lower the risk of
peptic ulcer bleeding associated with immunosuppressive agents.
However, PPIs represent a risk factor for bleeding from the small
intestine, hip fracture and cardiac events (34,35). It
is therefore recommended that long-term use of PPIs is avoided
(36). With this regard, H2RAs may
be recommended for long-term administration to prevent peptic ulcer
bleeding.
A major limitation is that the present study was
based on a relatively small number of patients. This may explain
why no correlation was found between NSAIDs, corticosteroids,
immunosuppressive agents and upper GI bleeding. In future studies,
a larger number of patients should be enrolled and studied.
In conclusion, the present study revealed that
immunosuppressive agents were correlated with peptic ulcer
bleeding. However, PPIs were effective at lowering the risk of
peptic ulcer bleeding.
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