ORIGINAL ARTICLE

Ankylosing spondylitis in Ireland: patient access and responseto TNF-a blockers

Aamir Saeed

Received: 13 August 2010 / Accepted: 16 January 2011 / Published online: 1 February 2011

� Springer-Verlag 2011

Abstract To investigate a group of Irish ankylosing

spondylitis patients: current prescription practice for TNF

blockers and patient response. All patients presenting with

ankylosing spondylitis (AS) and treated with TNF-alpha

between January 2006 and 2008 in the midwestern region

of Ireland were studied. Response was evaluated using

Bath Ankylosing Spondylitis Disease Activity Index

(BASDAI), Bath Ankylosing Spondylitis Functional Index

(BASFI), and CRP results at 6 months. A total of 47 AS

patients (32 men: 15 women, mean age 37.7 years, median

disease duration 20 years, 80% HLA B27 positive) were

identified; 66% were on disease-modifying anti-rheumatic

drugs (DMARDs) concomitantly. All patients satisfied

BSR/ASAS disease severity criteria for TNF-alpha at

baseline, and mean BASDAI was 6.2, BASFI 6.9, and CRP

27.5 mg/L. At 6 months, these had reduced to a mean

BASDAI of 3.8, BASFI 4.6, and CRP of 8.9 mg/L. Patients

with advanced AS (disease duration [10 years, mean

BASFI 7.5) responded at least as well. No allergies or

serious side effects were encountered, and one patient

successfully switched TNF agent due to secondary failure.

Initial good responses at 6 months were seen to be main-

tained in sub-group analysis at 12 months. Disease severity

in patients gaining access to treatment for active AS with

TNF blockers in Ireland is very high. Patients mainly sat-

isfy international guidelines for the use of biologics (BSR,

EULAR) with some minor exceptions. High disease

activity and long disease duration may predict better

treatment response. Response rates were good and treat-

ment was well tolerated, and no differences in response

were noted between the 3 agents employed.

Keywords Ankylosing spondylitis � Anti-TNF-a �Response � Outcome � DMARDs

Introduction

Ankylosing spondylitis (AS) is a condition characterized

by inflammatory back pain and associated with consider-

able disability and diminished quality of life in affected

individuals [1–4]. New pathogenic insights have identified

the key role of TNF-alpha in inflammatory rheumatic dis-

eases and have revolutionized the therapy of spondyloar-

thritis like AS. The ability of anti-TNF treatment to

dramatically suppress symptoms in AS and improve quality

of life is now beyond any doubt [5]. In the past decade,

these agents have been responsible for a sea change in the

prognosis for patients with AS, as not only are they highly

affective but previously there were no effective disease-

modifying treatments for AS.

TNF blockers specifically inhibit the proinflammatory

effects of TNF-alpha. Clinical studies with TNF blockers in

AS or related diseases have demonstrated superior efficacy

to conventional drugs like non-steroidal anti-inflammatory

drugs or disease-modifying anti-rheumatic drugs [1–5].

These targeted therapies have shown rapid and consistent

effectiveness in reducing the axial and peripheral symp-

toms of AS, slowing disease progression, and improving

patient functional status and quality of life [6–8].

However, the high costs and potentially serious side effects

[9], combined with uncertainties over any long-term ‘disease

modifying’ effects [10], make careful selection of patients for

treatment absolutely critical. Guidelines are currently avail-

able from both the ASAS/EULAR working group [11] and the

British Society of Rheumatology (BSR) [12] for criteria

defining patient groups eligible for TNF-alpha.

A. Saeed (&)

Limerick, Ireland

e-mail: modelian@gmail.com

123

Rheumatol Int (2012) 32:1305–1309

DOI 10.1007/s00296-011-1797-y

Currently, no Irish data is available regarding the

application, efficacy and safety of biologic usage in AS and

in the absence of specific Irish national guidelines for the

use of biological therapies in AS local criteria are generally

applied, guided primarily by physician opinion. According

to the ASAS/EULAR working group [11] and the British

Society of Rheumatology (BSR) [12] guidelines, TNF

blockers should be offered to patients who fulfill modified

New York criteria for AS with active disease [defined as a

Bath Ankylosing Spondylitis Disease Activity Index

(BASDAI) [4 on at least two occasions, 4 weeks apart]

and who have failed adequate therapeutic trials of at least

two NSAIDS.

Here, we study for the first time our clinical experience

with a cohort of AS patients in Ireland receiving TNF-

blocking therapy.

Materials and methods

A retrospective analysis of all patients with AS treated with

TNF-blocking drugs from the Midwestern regional hospital

and Croom Orthopedic hospital, Croom, Co. Limerick

between 2006 and 2008 were selected. All patients who

received TNF-blocking agents for 12 weeks or more were

included for analysis. Currently, patient selection for bio-

logical therapy is made based on consultant rheumatologist

opinion. Patients were continued on stable doses of non-

steroidal anti-inflammatory drugs (NSAIDS) and cortico-

steroids (\10 mgs daily).

The majority of the cohort had a diagnosis of AS sat-

isfying modified New York criteria [13]. A minority of

patients who had a combination of early inflammatory back

pain, HLA-B27 positivity and MRI evidence of sacroiliac

bone edema, who did not satisfy New York criteria were

included as these criteria have been shown to be associated

with a high probability of progressing to AS in future [14]

and recently published ASAS guidelines would allow their

inclusion [15].

The study received local ethics committee approval and

following informed written consent, clinical and laboratory

data were collected prospectively for all the AS patients

included in the cohort. These included demographics, dis-

ease duration, HLA-B27 status, Bath Ankylosing Spondy-

litis Disease Activity Index (BASDAI), Bath Ankylosing

Spondylitis Functional Index (BASFI), and CRP levels.

The primary outcome measure was to assess mean

improvement in BASDAI and secondary outcome mea-

sures BASFI and CRP, at 6 months post-TNF treatment.

Individual improvements in the BASDAI and BASFI and

CRP were also assessed.

In addition, any reason for discontinuation of therapy

was documented. Standard doses of TNF blockers used

were: Infliximab 5 mg/kg at baseline, week 2 then every

6 weeks, Etanercept 50 mg weekly, and Adalimumab

40 mg fortnightly.

Data are presented as percentage of improvement. Sig-

nificance testing was done using a one-way analysis of

variance test. A P value of B0.05 was considered as sta-

tistically significant.

Results

A total of 47 AS patients (32 men: 15 women, mean age

37.7 years, median disease duration 20 years, 80% HLA

B27 positive) were identified and received Anti-TNF ther-

apy (Infliximab 17, Etanercept 18, Adalimumab 12). The

demographics of the cohort are similar to those of other AS

cohorts (Table 1). A proportion of patients (66%) were

receiving concurrent DMARDs in the form of methotrexate

(100%) for peripheral arthritis and enthesitis in addition to

their biologics. None were taking Sulphasalazine or Leflu-

namide. About 66% of patients were on NSAIDS and the

majority of these were on Etoricoxib (41%).

All patients satisfied BSR guidelines for the prescription

of TNF blockers in relation to disease activity as measured

by BASDAI but that the majority (68%) had received/

Table 1 Baseline demographics of the AS (Irish) cohort prescribed

biologic drugs

M: F ratio 32: 15

Mean age (years) 37.7

Median disease duration (years) (range) 20 (1–33)

HLA-B27 positivity (%) 80

Associated peripheral arthritis (%) 36

Concomitant DMARDs (%) 66

MTX 100

SSZ 0

AZA 0

Concomitant NSAIDS (%) 66

Etoricoxib 41

Diclofenac 33

Others 26

Mean BASDAI 6.2

Mean BASFI 6.9

Mean CRP (mg/L) 27.5

Number of biologic drugs prescribed per patient (%)

1 46

2 1

Drugs used (no. of people prescribed drug)

Infliximab 17

Etanercept 18

Adalimumab 12

1306 Rheumatol Int (2012) 32:1305–1309

123

failed only one NSAID instead of two, and BASDAI

readings were taken at one time point instead of two time

points 4 weeks apart as per BSR guidelines. At base-

line, mean BASDAI was 6.2, BASFI 6.9, and CRP of

27.5 mg/L. At 6 months, these values had reduced to a

mean BASDAI of 3.85, BASFI 4.6, and CRP of 8.9 mg/L

(Fig. 1). One patient experienced secondary drug failure

and switched successfully to a second TNF blocker.

All patients were assessed for clinical response (patient

and physician global score) and BSR criteria response

(reduction in BASDAI of 50% or 2 points). Only 2 patients

failed to satisfy BSR response criteria. In these two cases,

BASDAI reduced from 4.1 at baseline to 3 and 5.2 to 3.6,

respectively. However, all patients experienced a good

clinical response. No allergies or serious side effects

requiring cessation or switch of therapy were noted. Further

analysis of data for differing of responses between various

treatments was undertaken. There were no significant dif-

ferences seen in outcome (BASDAI, BASFI, and CRP)

among the 3 individual biologic therapies (Figs. 2, 3).

A sub-group analysis was undertaken to look at patients

with a long disease duration in order to determine whether

this was associated with high disease activity and or

worsening levels of function and further whether this

would result in attenuated response to therapy. Nine

patients had a disease duration of [10 years (6 patients

[15 years). In this sub-group, the BASDAI was margin-

ally higher than the whole cohort at 6.4 and the BASFI as

one may have expected was very high at 7.5. CRP was also

high and higher than the whole cohort at 40 mg/L. Despite

this, response rates were excellent and if anything better

than in the group as a whole. BASDAI improved to 3.6

(56%), BASFAI to 4.78 (64%), and CRP levels returned to

normal (9.4 mg/L) (Fig. 4). A follow-up sub-group analy-

sis (32 patients: 20 men/12 women) at 12 months demon-

strated continued good clinical response with a mean

BADAI of 3.7, BASFI 4.4, and CRP of 6.1 mg/L.

Discussion

Anti-TNF therapy is highly effective in AS. Based on

published data for several thousand AS and psoriatic

arthritis patients, this treatment seems to be even more

effective than the same therapy in rheumatoid arthritisFig. 1 BASDAI, BASFI, and CRP in patients before and after

treatment with TNF antagonist

Fig. 2 Change in BASDAI after Infliximab, Etanercept, and Adali-

mumab

Fig. 3 Change in BASFI after Infliximab, Etanercept, and Adali-

mumab

Fig. 4 BASDAI, BASFI, and CRP in long standing patients

([10 years disease) before and after treatment with TNF antagonist

Rheumatol Int (2012) 32:1305–1309 1307

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(RA). Recently, there have also been a number of reports

looking at longer term follow-up of open label trial

extensions [16–18]. To date, however, there have been no

data looking at the use of anti-TNF therapy in an Irish AS

population. Questions remain as to the relative disease

severity of AS patients in this population when compared

to those in the United Kingdom and elsewhere. Also there

are no specific Irish guidelines as to which patients should

receive these drugs and no Irish national data base avail-

able for data collation and follow-up. Consequently, cur-

rent practice may be presumed to vary across regions and

between physicians whose clinical opinion is the primary

determinant of which patients are deemed to require TNF

blockers. Rheumatologists in Ireland are generally trained

within the national system or in the United Kingdom or in

America. It may be that prescription patterns reflect those

adopted within these health systems and also those adopted

by the ASAS/EULAR working group. This study presents

for the first time data that goes some way to addressing

these questions.

The cohort of patients identified is similar to groups in the

United Kingdom and elsewhere who have received TNF.

The mean disease activity, functional index, and CRP are

comparable to those receiving biologics in the United

Kingdom [5]. Interestingly, all patients satisfied stringent

BSR requirements for biologics in terms of disease severity

and activity. In a health care setting where physician opinion

guides therapy, it may have been argued that some patients

with lower disease activity were more likely to receive these

agents despite major cost implications. This however has not

been evident. The cohort presented is of course for one

region of the country and is not necessarily representative of

the national picture of TNF prescription, but it does indicate

that in general the criteria applied to prescription decisions

are qualitatively similar to those made in a guideline man-

aged system such as the United Kingdom.

Switching of TNF blockers following secondary failure

occurred in only one patient and was successful. This is

significantly less than the 8% presented by Coates et al. [5].

However, the mean time of follow-up that study was

21 months as opposed to 6 months in this group so it may

be presumed that further episodes of secondary failure may

occur with time. In relation to patient response, it is dem-

onstrated that all patients experienced an excellent

response. Two patients failed to meet stringent BSR

response criteria, however, but both reported a patient

reported response of greater than 50% perhaps reflecting

limitations in the response criteria rather than lack of

benefit. Certainly it would not be acceptable to discontinue

TNF therapy in either patient on pure clinical grounds, and

this must raise questions of the validity of strictly applying

these response criteria when allowing continued treatment

in some patients.

Treatments were well tolerated with no significant side

effect episodes. All 3 agents were highly effective, and this

again reflects previously published data [5–8]. A very

interesting sub-group we studied was those with long dis-

ease duration. There have been 2 main questions raised

about the treatment of these patients: (1) Are these patients

‘‘burned out’’ in that the damage has been done and the

inflammatory component of their disease which is so

effectively turned off by TNF therapy has gone or (2) The

inflammation is now irrelevant as the damage (fusion) has

been done and patients will not benefit. Recently Rudwaleit

et al. addressed many of these issues looking at patients

with high-grade Steinbrocker scores (IV and V) [19]. Our

sub-group of severe patients are defined by their long

disease duration ([10 years), but this is reflected in high

BASDAI of 6.4 and very high BASFI of 7.5. These figures

are comparable to Rudwaleit’s group with Steinbrocker

Stage V (BASDAI = 6.5, BASFI = 7.0). Similarly, we

demonstrated that these patients not only responded very

well to TNF blockers but in fact response rates were greater

than in the cohort as a whole. Many studies have excluded

patients with bamboo spine on the grounds that they cannot

respond, but there is evidence that this is not the case. It

appears that in many patients, even with bony fusion, a

degree of functional loss may be due to persistent inflam-

matory tissue and this is responsive to therapy. In severe

damage and deformity, even apparently modest improve-

ments in movement and measurements may afford major

benefits for the patient who may be able to look forwards

when walking or look sideways with some neck rotation

and this may prevent the need for surgery such as spinal

osteotomy. The presence of a high BASDAI, reversible

early morning stiffness with steroids and a high CRP are all

indicators of possible reversible inflammation and in our

practice warrant a trial of TNF therapy [19]. This is not to

state however that all severe long-term disease patients will

benefit from TNF treatment. There are those who appear to

fuse completely within a short time of disease onset with a

consequent switching off of the inflammatory process.

These patients are characterized by an absence of the

features noted above.

In summary, it appears that Irish patients receiving

TNF-blocking therapies for AS have similar demographics

and disease activity to those in the United Kingdom despite

the lack of any national guidelines or TNF/Biologics data

base. Patients experienced excellent response rates and

treatment was safe and well tolerated. We provide further

evidence that severely disabled patients with long disease

duration and high activity should not only be considered

for treatment, but appear to benefit even more than in

general. However, this cohort does not represent the Irish

population as a whole, and we would strongly support the

development of a national Biologics data base for AS.

1308 Rheumatol Int (2012) 32:1305–1309

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