SPANISH REGISTRY OF ADVERSE EVENTS OF BIOLOGICAL THERAPIES IN
RHEUMATIC DISEASES
(Phase II)
DECEMBER 2013 REPORT
December 2013
Table of Contents
Table of Contents ............................................................................................... Error! Bookmark not defined.
Description of the registry with all the biological therapies .............................. Error! Bookmark not defined.
Table 1.- Description of patients included in BIOBADASER 2.0.Error! Bookmark not defined.
Table 2.- Description of biological therapies. ........................................................................... 4
Table 3.- Frequency of adverse events by groups. .................................................................. 5
Table 4.- Frequency of serious adverse events. ...................................................................... 6
Table 5.- Frequency of fatal adverse events. ........................................................................... 7
Table 6.- Incidence rate of adverse events. ............................................................................. 7
Table 7.- Incidence rate of serious adverse events. ................................................................ 8
APPENDIX ........................................................................................................... Error! Bookmark not defined.
Table I.- Itemized frequencies of fatal adverse events ............ Error! Bookmark not defined.
2
All biological agents
December 2013
Description of the registry with all the biological therapies
BIOBADASER 2.0 dataset was last updated on December 16th. Fourteen centers are participating in this project (due
to work overload, the Hospital la Fe in Valencia, Spain, ended its participation in 2010, as did the Hospital de la
Princesa and Hospital 12 de Octubre in Madrid, Spain, both at the beginning of 2013). As of today, 6,891 patients
have been included, totaling the administration of 23,462 cycle treatments. See Table 1 for a description of the
patients included.
Table 1—Description of patients included in BIOBADASER 2.0.
All biological agents
Number of patients (%)
6,891
Women (%)
4,279 (62.1)
Mean age (SD)
56.3 (15.6)
Mean age as of first biological treatment start (SD)
49.6 (15.2)
Median time (in years) (P50) since disease onset by beginning of treatment [P25-P75]
8.9 [4.0-15.9]
Diagnosis
n (%)
n (%)
Rheumatoid Arthritis
3,516 (51.0)
Juvenile AD
20 (0.3)
Ankylosing Spondylitis
1,120 (16.2)
Polymyositis / Dermatomyositis
17 (0.2)
Psoriatic Arthritis or SpA
1,106 (16.0)
Juvenile Undifferentiated Spondyloarthritis
17 (0.2)
Undifferentiated Spondyloarthropathy
286 (4.1)
Reactive Arthritis
15 (0.2)
Juvenile Idiopathic Arthritis
266 (3.9)
SAPHO syndrome
15 (0.2)
Enteropathic Arthritis
132 (1.9)
Recidivant Polychondritis
10 (0.1)
Systemic Lupus Erythematosus
57 (0.8)
Scleroderma
9 (0.1)
Behçet’s Disease
45 (0.6)
Psoriasis
9 (0.1)
Seronegative Chronic Polyarthritis
44 (0.6)
Sarcoidosis
8 (0.1)
Overlap
42 (0.6)
Pyoderma Gangrenosum
2 (0.0)
Seronegative Chronic Oligoarthritis
37 (0.5)
Muckle-Wells syndrome
2 (0.0)
Uveitis with no Rheumatic Disease
36 (0.5)
Felty syndrome
1 (0.0)
Vasculitis
26 (0.4)
Epidermolysis Bullosa
1 (0.0)
Primary Sjögren’s Syndrome
25 (0.4)
Hidrosadenitis Suppurativa
1 (0.0)
Still’s Disease
25 (0.4)
CINCA syndrome
1 (0.0)
Total
6,891 (100.0)
Abreviations: SD, standard deviation; SpA, spondyloarthritis
The registry consists mainly of middle-aged women with a median disease progression before beginning biologic
treatment of 8.9 years with an interquartile range of 11.9 years. The most frequent diagnosis is rheumatoid arthritis
(51.0%), followed by ankylosing spondylitis (16.2%), and psoriatic arthritis (16,0%).
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All biological agents
December 2013
Table 2 shows the description of the treatments. We divided the data according to whether therapy was used as the
first treatment option, or as second option or a later option, i.e. the patient had had at least one prior biological
therapy which was discontinued, except for rituximab, for which, given its protocol, second cycles are considered,
even when treatment has not been suspended. From all treatment cycles reported, 57.8 % (13,559) are biologics
used as the first treatment option.
Table 2—Description of biological treatments
Biological agent
First option
treatment
n (%)
As second or later
option treatment
n (%)
All
n (%)
Etanercept
3,674 (27.1)
2,789 (28.2)
6,463 (27.5)
Infliximab
6,180 (45.6)
1,099 (11.1)
7,279 (31.0)
Adalimumab
2,863 (21.1)
2,101 (21.2)
4,964 (21.2)
Rituximab*
283 (2.1)
2,290 (23.1)
2,573 (11.0)
Tocilizumab
315 (2.3)
686 (6.9)
1,001 (4.3)
Abatacept
109 (0.8)
543 (5.5)
652 (2.8)
Golimumab
61 (0.4)
239 (2.4)
300 (1.3)
Anakinra
42 (0.3)
81 (0.8)
123 (0.5)
Certolizumab
32 (0.2)
60 (0.6)
92 (0.4)
Canakinumab
0 (0.0)
10 (0.1)
10 (0.0)
Ocrelizumab
0 (0.0)
4 (0.0)
4 (0.0)
Belimumab
0 (0.0)
1 (0.0)
1 (0.0)
Treatment Cycles
13,559 (100.0)
9,903 (100.0)
23,462 (100.0)
Reason for discontinuation
n (%)
n (%)
n (%)
Adverse Event
3,257 (42.2)
1,880 (28.2)
5,137 (35.7)
Inefficacy or loss of efficacy
2,557 (33.1)
1,912 (28.7)
4,469 (31.1)
989 (12.8)
2,461 (36.9)
3,449 (24.0)
Remission
365 (4.7)
76 (1.1)
441 (3.1)
Patient Lost to Follow-Up
305 (3.9)
132 (2.0)
437 (3.0)
Pregnancy or Desire to be Pregnant
210 (2.7)
110 (1.6)
320 (2.2)
Unknown
33 (0.4)
93 (1.4)
126 (0.9)
Total Number of Discontinuations
7,715 (100.0)
6,664 (100.0)
14,379 (100.0)
Other
#
* Includes each cycle administered, even when treatment was not discontinued; # End of rituximab cycle, not a specific reason for discontinuation.
Biologic agents most frequently used as first option are infliximab (45.6%) and etanercept (27.1%). Rituximab
(27.6%), etanercept (27.2%), and adalimumab (20.2%) are the ones most often used as the second or later
treatment option. The substantial increase in the use of rituximab as second or later biologic treatment option is due
to its different administration protocol. Two cycles of rituximab 6 months apart—the usual timeline for this
biologic— are considered separate treatments, unlike with infliximab, as an example of another intravenously
administered biologic. Tocilizumab and Golimumab increase their utilization.
4
All biological agents
December 2013
Among the reasons for discontinuation of treatment with the first-option biologic, occurrence of an adverse event is
the most reported one accounting for 42.2% of the time, followed by inefficacy or loss of efficacy (33.1%). In second
or later treatments, disregarding the category “other” which refers to the end of rituximab cycle, it is the inefficacy
or loss of efficacy (28.7%) and adverse events (28.2%).
As mentioned above, the increase in the “other” category is due to the method of administering and registering
rituximab treatments, which includes the end of a regular cycle with no issues to report.
Table 3 summarizes the frequency and percentage of the different adverse events reported by large organ and
systems groups (MedDRA). The most common ones are infections and infestations, accounting for 35.6% of all
recorded adverse events, followed by general disorders and administration site reactions with 7.4%.
Table 3—Frequency of adverse events by group
Adverse Events (AE)
n
% of total AE
Infections and infestations
5,879
35.6
General disorders and administration site reactions
1,227
7.4
Skin and subcutaneous tissue disorders
1,080
6.5
Additional patient investigations
794
4.8
Gastrointestinal disorders
751
4.5
Musculoskeletal and connective tissue disorders
696
4.2
Nervous system disorders
650
3.9
Injury, poisoning and complications from treatment procedures
571
3.5
Surgical and medical procedures
528
3.2
Eye disorders
492
3.0
Respiratory, thoracic and mediastinal disorders
474
2.9
Blood and lymphatic system disorders
417
2.5
Neoplasms benign, malignant and unspecified (included cysts and polyps)
415
2.5
Vascular disorders
399
2.4
Cardiac disorders
379
2.3
Renal and urinary disorders
359
2.2
Metabolism and nutrition disorders
314
1.9
Psychiatric disorders
243
1.5
Hepatobiliary disorders
232
1.4
Reproductive system and breast disorders
160
1.0
Ear and labyrinth disorders
100
0.6
Pregnancy, puerperium and perinatal conditions
92
0.6
Endocrine disorders
89
0.5
Immune system disorders
63
0.4
Congenital, familial and genetic disorders
57
0.3
Social circumstances
29
0.2
Total
16,490
100.0
5
All biological agents
December 2013
Of the adverse events recorded, 81.9% (13,501) were classified as "non-serious," 17.0% (2,799) were reported as
"serious," and 1.1% (190) were "fatal."
Table 4 shows the frequency of reported serious adverse events. The most common are still infections and
infestations, followed by cardiac disorders and neoplasms.
Table 4—Frequency of serious adverse events
Serious Adverse Events (SAE)
n
% of total SAE
Infections and infestations
937
33.5
Neoplasms benign, malignant and unspecified (included cysts and polyps)
224
7.9
Cardiac disorders
218
7.8
Surgical and medical procedures
184
6.76
Injury, poisoning and complications from treatment procedures
156
5.5
General disorders and administration site reactions
142
5.1
Nervous system disorders
138
5.0
Respiratory, thoracic and mediastinal disorders
130
4.6
Gastrointestinal disorders
112
4.0
Renal and urinary disorders
75
2.7
Vascular disorders
73
2.6
Musculoskeletal and connective tissue disorders
63
2.2
Blood and lymphatic system disorders
55
2.0
Skin and subcutaneous tissue disorders
52
1.9
Eye disorders
42
1.5
Hepatobiliary disorders
40
1.4
Psychiatric disorders
31
1.1
Metabolism and nutrition disorders
28
1.0
Immune system disorders
25
0.9
Additional patient investigations
23
0.8
Pregnancy, puerperium and perinatal conditions
20
0.7
Reproductive system and breast disorders
12
0.4
Endocrine disorders
7
0.2
Congenital, familial and genetic disorders
5
0.2
Social circumstances
4
0.1
Ear and labyrinth disorders
3
0.1
Total
2,799
100.0
Table 5 shows the frequency and proportion of fatal adverse events by System Organ Classes. Most common causes
of death were infections (30.3%), especially pneumonia (2.9%) and sepsis (3.4%). Neoplasms (25.5%) are the second
largest group of fatal events followed by cardiac disorders (13.0%), and general disorders (11.5%).
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All biological agents
December 2013
General disorders are found among the fatal adverse events because MedDRA encodes deaths by unknown cause
under this category. A table in the appendix lists all the deaths reported in BIOBADASER 2.0.
Table 5—Frequency of fatal adverse events
Fatal adverse events (FAE)
n
% of total FAE
Infections and infestations
63
30.3
Neoplasms benign, malignant and unspecified (included cysts and polyps)
53
25.5
Cardiac disorders
27
13.0
General disorders and administration site reactions
24
11.5
Nervous system disorders
11
5.3
Respiratory, thoracic and mediastinal disorders
11
5.3
Gastrointestinal disorders
7
3.4
Vascular disorders
2
1.0
Injury, poisoning and complications from treatment procedures
2
1.0
Blood and lymphatic system disorders
2
1.0
Hepatobiliary disorders
2
1.0
Surgical and medical procedures
1
0.5
Renal and urinary disorders
1
0.5
Immune system disorders
1
0.5
Psychiatric disorders
1
0.5
Total*
208
100.0
* A total of 190 patients died, but some patients suffered more than one fatal adverse event.
Table 6 shows the incidence rate of all adverse events, by System Organ Classes. Total incidence rate is 412.3 (406.1418.7) adverse events per 1,000 patient-years. For serious adverse events the incidence rate is 70.0 (67.4-72.6) and
for fatal adverse events the incidence rate is 4.7 (4.1-5.5) per 1,000 patient-years.
Table 6—Incidence rate of adverse events
Incidence Rate (95% CI) /x 1,000 patient-years
First option
treatment
Second and later
option treatments
Total
All adverse events
464.5 (455.7-473.4)
447.1 (435.7-458.4)
412.3 (406.1-418.7)
Serious
76.2 (72.7-79.9)
80.5 (75.7-85.5)
70.0 (67.4-72.6)
Fatal
5.2 (4.3-6.2)
5.4 (4.2-6.8)
4.7 (4.1-5.5)
Infections and infestations
167.5 (162.2-172.9)
156.1 (149.4-163.0)
147.0 (143.3-150.8)
General disorders and administration site conditions
35.4 (33.0-38.0)
32.0 (28.7-34.9)
30.7 (29.0-32.4)
Skin and subcutaneous tissue disorders
30.9 (28.7-33.3)
28.4 (25.6-31.5)
27.0 (25.4-28.6)
By System Organ Classes
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All biological agents
December 2013
Incidence Rate (95% CI) /x 1,000 patient-years
First option
treatment
Second and later
option treatments
Total
Gastrointestinal disorders
23.7 (21.8-25.8)
19.1 (16.8-21.6)
19.8 (18.5-21.3)
Nervous system disorders
19.7 (17.9-21.6)
22.8 (20.3-25.6)
18.8 (17.5-20.2)
Additional patient investigations
19.2 (17.5-21.1)
19.5 (17.2-22.0)
17.4 (16.1-18.7)
Cardiac disorders
18.1 (16.4-19.9)
18.0 (15.8-20.5)
16.2 (15.0-17.5)
Musculoskeletal and connective tissue disorders
15.1 (13.6-16.8)
17.1 (14.9-19.5)
14.3 (13.1-15.5)
Neoplasms benign, malignant and unspecified (included
cysts and polyps)
13.9 (12.4-15.5)
16.0 (13.9-18.4)
13.2 (12.1-14.4)
Respiratory, thoracic and mediastinal disorders
13.3 (11.9-14.9)
14.3 (12.3-16.5)
12.3 (11.2-13.4)
Vascular disorders
12.3 (10.9-13.9)
14.6 (12.6-16.8)
11.8 (10.8-12.9)
Blood and lymphatic system disorders
10.5 (9.2-11.9)
13.5 (11.6-15.7)
10.4 (9.4-11.5)
Surgical and medical procedures
14.3 (12.8-15.9)
6.6 (5.3-8.2)
10.4 (9.4-11.4)
Injury, poisoning and procedural complications
12.3 (10.9-13.8)
9.0 (7.5-10.8)
10.0 (9.0-11.0)
Eye disorders
10.6 (9.3-12.1)
10.3 (8.6-12.2)
9.5 (8.5-10.5)
Renal and urinary disorders
9.8 (8.6-11.2)
14.6 (12.6-16.8)
11.8 (10.8-13.0)
Hepatobiliary disorders
8.7 (7.5-10.0)
8.8 (7.2-10.5)
7,8 (7,0-8,7)
Psychiatric disorders
6.5 (5.5-7.7)
7.1 (5.7-8.7)
6.1 (5.3-6.9)
Reproductive system and breast disorders
5.9 (5.0-7.0)
7.3 (6.0-9.0)
5.8 (5.1-6.6)
Immune system disorders
4.7 (3.9-5.7)
3.9 (2.9-5.1)
4.0 (3.4-4.7)
Metabolism and nutrition disorders
2.7 (2.1-3.5)
2.8 (2.0-3.9)
2.5 (2.0-3.0)
Endocrine disorders
2.3 (1.7-3.0)
3.0 (2.1-4.0)
2.3 (1.8-2.8)
Ear and labyrinth disorders
2.5 (1.9-3.2)
2.4 (1.7-3.4)
2.2 (1.8-2.7)
Pregnancy, puerperium and perinatal conditions
1,5 (1,0-2,0)
2,2 (1,5-3,2)
1,6 (1,2-2,0)
Congenital, familial and genetic disorders
1.7 (1.2-2.3)
1.4 (0.8-2.2)
1.4 (1.1-1.8)
Social circumstances
0.9 (0.6-1.4)
0.6 (0.3-1.2)
0.7 (0.5-1.0)
Table 7 shows the incidence rate of those adverse effects considered serious by the researchers. Serious infections
and infestations presented an incidence rate of 23.4 (21.9-25.0) serious adverse events per 1,000 patient-years.
Incidence rate for cardiac disorders and neoplasms are 5.4 (4.9-6.4) and 5.6 (4.9-6.4) per 1,000 patient-years,
respectively.
Table 7—Incidence rate of serious adverse events
Incidence Rate (95% CI) /x 1,000 patient-years
First option
treatment
Second and later
option treatments
Total
Infections and infestations
25.7 (23.6-27.8)
26.7 (23.9-29.6)
23.4 (21.9-25.0)
Neoplasms benign, malignant and unspecified (included cysts
and polyps)
7.6 (6.5-8.8)
3.7 (2.8-4.9)
5.6 (4.9-6.4)
Cardiac disorders
6.2 (5.3-7.3)
5.7 (4.4-7.1)
5.4 (4.7-6.2)
Surgical and medical procedures
4.8 (4.0-5.8)
5.6 (4.4-7.0)
4.6 (4.0-5.3)
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All biological agents
December 2013
Incidence Rate (95% CI) /x 1,000 patient-years
First option
treatment
Second and later
option treatments
Total
Injury, poisoning and procedural complications
4.1 (3.3-5.0)
4.7 (3.6-6.1)
3.9 (3.3-4.6)
General disorders and administration site conditions
3.4 (2.7-4.2)
4.9 (3.8-6.2)
3.5 (3.0-4.2)
Nervous system disorders
3.6 (2.8-4.4)
4.3 (3.2-5.6)
3.4 (2.9-4.1)
Respiratory, thoracic and mediastinal disorders
3.1 (2.4-3.9)
4.6 (3.5-5.9)
3.2 (2.7-3.9)
Gastrointestinal disorders
2.7 (2.1-3.5)
3.7 (2.8-4.9)
2.8 (2.3-3.4)
Renal and urinary disorders
2.1 (1.6-2.8)
2.0 (1.3-2.9)
1.9 (1.5-2.3)
Vascular disorders
2.3 (1.7-3.0)
1.6 (1.0-2.4)
1.8 (1.4-2.3)
Musculoskeletal and connective tissue disorders
1.5 (1.1-2.1)
2.1 (1.4-3.1)
1.6 (1.2-2.0)
Blood and lymphatic system disorders
1.0 (0.7-1.6)
2.4 (1.6-3.4)
1.4 (1.0-1.8)
Skin and subcutaneous tissue disorders
1.1 (0.7-1.7)
2.0 (1.3-2.9)
1.3 (1.0-1.7)
Eye disorders
0.8 (0.5-1.2)
1.8 (1.2-2.7)
1.0 (0.8-1.4)
Hepatobiliary disorders
1.0 (0.6-1.5)
1.3 (0.8-2.1)
1.0 (0.7-1.4)
Psychiatric disorders
0.8 (0.5-1.3)
0.9 (0.5-1.6)
0.8 (0.5-1.1)
Metabolism and nutrition disorders
0.8 (0.5-1.2)
0.8 (0.4-1.4)
0.7 (0.5-1.0)
Immune system disorders
0.5 (0.3-0.9)
1.0 (0.5-1.7)
0.6 (0.4-0.9)
Additional patient investigations
0.7 (0.4-1.1)
0.5 (0.2-1.1)
0.6 (0.4-0.9)
Pregnancy, puerperium and perinatal conditions
0.5 (0.2-0.9)
0.7 (0.3-1.3)
0.5 (0.3-0.8)
Reproductive system and breast disorders
0.3 (0.1-0.7)
0.3 (0.1-0.8)
0.3 (0.1-0.5)
Endocrine disorders
0.2 (0.1-0.5)
0.1 (0.0-0.5)
0.2 (0.1-0.4)
Congenital, familial and genetic disorders
0.1 (0.0-0.3)
0.2 (0.0-0.7)
0.1 (0.0-0.3)
Social circumstances
0.1 (0.0-0.3)
0.1 (0.0-0.5)
0.1 (0.0-0.3)
Ear and labyrinth disorders
0.1 (0.0-0.3)
0.1 (0.0-0.4)
0.1 (0.0-0.2)
9
All biological agents
APPENDIX
Table I— Itemized frequencies of fatal adverse events
Fatal adverse events (FAE)
n
% of total FAE
Infections and infestations
63
30.3
Sepsis
7
3.4
Pneumonia
6
2.9
Septic shock
4
1.9
Lower respiratory tract infection
3
1.5
Disseminated tuberculosis
3
1.5
Staphylococcal sepsis
3
1.5
Pulmonary tuberculosis
2
1.0
Peritoneal infection
2
1.0
Upper respiratory tract infection
2
1.0
Endocarditis staphylococcal
2
1.0
Lymph node tuberculosis
1
0.5
Sepsis due to escherichia coli (E. coli)
1
0.5
Bacterial pyelonephritis
1
0.5
Bacterial peritonitis
1
0.5
Pneumonia due to mycoplasma pneumoniae
1
0.5
Lobar pneumonia
1
0.5
Pneumonia due to escherichia coli (E. coli)
1
0.5
Lung infection
1
0.5
Escherichia coli infection
1
0.5
Cytomegalovirus infection
1
0.5
Acinetobacter infection
1
0.5
Wound infection staphylococcal
1
0.5
Enterococcal infection
1
0.5
Urinaty tract infection due to pseudomonas
1
0.5
Soft tissue infection
1
0.5
Infection
1
0.5
Visceral herpes simplex
1
0.5
Gastroenteritis clostridial
1
0.5
Infective spondylitis
1
0.5
Bacterial endocarditis
1
0.5
Diverticulitis
1
0.5
Vaginal candidiasis
1
0.5
Bronchopulmonary aspergillosis
1
0.5
December 2013
Fatal adverse events (FAE)
n
% of total FAE
Aspergillosis
1
0.5
Staphylococcus aureus infection induced septic arthritis
1
0.5
Liver abscess
1
0.5
Brain abscess
1
0.5
Neoplasms benign, malignant and unspecified (included cysts and polyps)
53
25.5
Metastases to bone
4
1.9
Pancreatic carcinoma
3
1.4
Prostate cancer
3
1.4
Adenosquamous cell lung cancer
3
1.4
Lung squamous cell carcinoma stage unspecified
2
1.0
Breast cancer
2
1.0
Metastatic lung cancer
2
1.0
Gastric cancer stage IV, without metastasis
2
1.0
Metastatic colorectal cancer
2
1.0
Nodular sclerosis Hodgkin disease
2
1.0
Metastases to abdominal cavity
2
1.0
Metastases to lung
2
1.0
Malignant lung neoplasm
2
1.0
Rectal neoplasm
2
1.0
Pancreatic carcinoma
1
0.5
Oesophageal carcinoma
1
0.5
Malignant neuroendocrine carcinoma
1
0.5
Metastatic pancreatic carcinoma
1
0.5
Non-resectable pancreatic carcinoma
1
0.5
Colorectal cancer stage II
1
0.5
Metastatic colorectal cancer
1
0.5
Non-resectable bile duct cancer
1
0.5
Breast cancer stage IV
1
0.5
Adenosquamous cell lung cancer stage IV
1
0.0
Metastatic fallopian tube cancer
1
5.0
Metastatic breast cancer
1
0.5
Acute myeloid leukemia
1
0.5
B-cell lymphoma
1
0.5
Metastases to liver
1
0.5
Mycosis fungoides stage IV
1
0.5
Multiple myeloma
1
0.5
Malignant neoplasm of orbit
1
0.5
General disorders and administration site conditions
24
11.5
Death
20
9.7
11
December 2013
Fatal adverse events (FAE)
n
% of total FAE
Sudden death
2
1.0
Condition aggravated
1
0.5
Sudden cardiac death
1
0.5
Cardiac disorders
27
13.0
Acute myocardial infarction
8
3.9
Cardiac failure congestive
3
1.5
Cardiopulmonary failure
3
1.5
Cardiac arrest
3
1.0
Cardiac failure chronic
2
1.0
Cor pulmonale acute
1
0.5
Electromechanical dissociation
1
0.5
Cardiac failure
1
0.5
Ventricular fibrillation
1
0.5
Myocardial infarction
1
0.5
Myocardial ischaemia
1
0.5
Cardio-respiratory arrest
1
0.5
Pericarditis
1
0.5
Nervous system disorders
11
5.3
Ischaemic stroke
2
1.0
Cerebrovascular accident
1
0.5
Neurodegenerative disorder
1
0.5
Anoxic encephalopathy
1
0.5
Amyotrophic lateral sclerosis (ALS)
1
0.5
Subdural haematoma
1
0.5
Cerebral haemorrhage
1
0.5
Intracranial haemorrhage
1
0.5
Haemorrhagic stroke
1
0.5
Lacunar infarction
1
0.5
Respiratory, thoracic and mediastinal disorders
11
5.3
Respiratory failure
2
1.0
Obliterative bronchiolitis
1
0.5
Pleural effusion
1
0.5
Pulmonary embolism
1
0.5
Interstitial lung disease
1
0.5
Pulmonary fibrosis
1
0.5
Acute respiratory failure
1
0.5
Pulmonary mass
1
0.5
Pneumothorax
1
0.5
Diffuse panbronchiolitis
1
0.5
12
December 2013
Fatal adverse events (FAE)
n
% of total FAE
Gastrointestinal disorders
7
3.4
Oesophageal variceal haemorrhage
1
0.5
Lower gastrointestinal haemorrhage
1
0.5
Upper gastrointestinal haemorrhage
1
0.5
Intestinal ischaemia
1
0.5
Bowel obstruction
1
0.5
Acute pancreatitis
1
0.5
Duodenal perforation
1
0.5
Surgical and medical procedures
1
0.5
Activation of macrophages
1
0.5
Injury, poisoning and procedural complications
2
1.0
Complications of intervention
1
0.5
Subdural haematoma
1
0.5
Blood and lymphatic system disorders
2
1.0
Bone marrow disorders
1
0.5
Bone marrow toxicity
1
0.5
Hepatobiliary disorders
2
1.0
Cirrhosis alcoholic
1
0.5
Hepatitis toxic
1
0.5
Renal and urinary disorders
1
0.5
Renal amyloidosis
1
0.5
Vascular disorders
2
1.0
Aortic aneurysm
1
0.5
Aortic aneurysm rupture
1
0.5
Immune system disorders
1
0.5
Primary amyloidosis
1
0.5
Psychiatric disorders
1
0.5
Completed suicide
1
0.5
Total
208
100.0
Madrid, December 2013
Research Unit of the Spanish Society of Rheumatology
13