Effectiveness of a rehabilitative programme in improving fatigue and function in rheumatoid arthriti

BRIEF PAPER

Effectiveness of a rehabilitative programme in improving fatigue and function in rheumatoid arthritis patients treated with biologics: a pilot study

L. Di Gioia1, C. Zincarelli1, M.N.D. Di Minno2,

G. Rengo3, R. Peluso4,

A. Spanò4, S. Iervolino1, N. Pappone1

1Rheumatology and Rehabilitation Research Unit, Salvatore Maugeri Foundation I.R.C.C.S. Scienti?c Institute of Telese Terme (BN) Italy;

2Reference Centre of Coagulation Disorders, Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy;

3Department of Cardiology, Salvatore Maugeri Foundation I.R.C.C.S. Scienti?c Institute of Telese Terme (BN) Italy;

4Rheumatology Research Unit, Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy. Luisa Di Gioia, MD

Carmela Zincarelli, PhD

Matteo Nicola Dario Di Minno, MD Giuseppe Rengo, PhD

Rosario Peluso, Professor

Angelo Spanò, MD

Salvatore Iervolino, MD

Nicola Pappone, MD

Please address correspondence to: Salvatore Iervolino, MD,

Clinica Riabilitazione Reumatologica, Salvatore Maugeri Foundation I.R.C.C.S., Via Bagni Vecchi 1,

Telese Terme (BN), Italy.

E-mail: calmodulina@inwind.it Received on August 7, 2012; accepted in revised form on October 3, 2012.

? Copyright C LINICAL AND

E XPERIMENTAL R HEUMATOLOGY 2013. Key words: rheumatoid arthritis, fatigue, rehabilitation, functional class.

Competing interests: none declared.ABSTRACT

Objective.To evaluate the effective-

ness of a personalised rehabilitative

programme in improving fatigue and

function in rheumatoid arthritis (RA)

female patients treated with biologic

DMARDs.

Methods.Thirty-eight consecutive fe-

male RA in-patients treated with bio-

logics, entered this prospective pilot

study. All subjects were in high disease

activity (DAS-28>5.1). After baseline

(T0) evaluation, a personalised 4-weeks

rehabilitative programme was added to

standard biologic treatment and all pa-

tients were re-evaluated at the end of

the rehabilitative treatment (T1), at 3

(T2), 6 (T3) and 9 (T4) month follow-

up. Clinical rheumatologic assessment

included the DAS-28, TJC, SJC, global

health status, HAQ and F ACIT.

Results.Subjects showed a mean age

of 65±3.5 years and a 10±1,1 years

mean disease duration. All clinical and

laboratory outcomes signi?cantly im-

proved at the different follow-up times

as compared to baseline. In particular,

a signi?cant improvement in function

and fatigue indices (HAQ and F ACIT)

was found since T1 to T4 as compared

to T0. During the follow-up, DAS-28

decreased. Accordingly, about 30% of

subjects achieved a moderate disease

activity (DAS-28<5.1).

Conclusion. A combined treatment

biologics-rehabilitation is effective in

improving function and fatigue in fe-

male patients with established RA. Fa-

tigue results independent from disease

activity.

Introduction

Rheumatoid arthritis (RA) represents

a major cause of disability secondary

to reduced muscle mass (rheumatoid

cachexia), joint damage and increased

adiposity (1). Muscle loss is associated

with impaired immune and pulmonary

function, osteoporosis, glucose intoler-

ance and increased mortality (1). There

is also extensive evidence that a series

of variables in?uence RA-related fa-

tigue (pain, functional status, gender

and disease duration) (1).Interventions

aimed to increase muscle mass in RA

patients may improve physical per-

formance and decrease morbidity and

mortality (2). Marcora et al.showed

that a 12-weeks high-intensity resist-

ance training signi?cantly improved

functional capacity in RA cachectic

patients (3). Similarly, Hakkinen et

al.found that combined strength and

aerobic training increased thigh mus-

cle mass and decreased thigh fat mass

in female RA patients (4). Nowadays,

many reports show that biologic agents,

particularly tumor necrosis factor-α

inhibitors, improve RA fatigue. How-

ever, conclusive data on the ef?cacy of

a combined biologic agents-rehabilita-

tion programme on fatigue and disease

activity in subjects with established

RA are currently lacking. Our study is

aimed to evaluate the effectiveness of a

personalised intensive rehabilitation in

reducing fatigue in female RA patients

in high disease activity and with func-

tion impairment, treated with biologic

DMARDs. The secondary end-point is

to assess the relationship disease activ-

ity-fatigue.

Methods

From December 2009 to November

2011, 38 consecutive female in-pa-

tients diagnosed with RA according to

the ACR 1987 revised criteria(5) non

responders to traditional therapies and

treated with biologic DMARDs, refer-

ring to the Rheumatology and Reha-

bilitation Research Unit of the “Salva-

tore Maugeri” Foundation entered this

prospective study. All subjects were in

high disease activity according to the

disease activity score (DAS-28>5.1)

and had been treated with a biologic

agent for at least 12 months. After in-

formed consent was given, a baseline

(T0) clinical evaluation was carried

out by a trained staff, including the 28-

joint Disease Activity Score (DAS-28)

according to ESR, tender joint count

(TJC), swollen joint count (SJC), glo-

bal health status (GH) and measures

of function and fatigue including the

Health Assessment Questionnaire

(HAQ), and FACIT (Functional As-

sessment of Chronic Illness Therapy).

Subjects were classi?ed according to

established criteria for the functional

loss into 4 classes (6). Functional class

(FC) I includes individuals without dif-

?culties in daily life, FC II includes

Clinical and Experimental Rheumatology 2013; 31: 285-288.

those with symptoms but minor limita-tions only, FC III includes those who are partly dependent, and FC IV in-cludes those who are totally dependent on other persons in daily life. Venous blood samples were collected to evalu-ate the erythrocyte sedimentation rate (ESR).

Exercise intervention

After baseline assessment, all subjects underwent a 4-week-lasting twice/daily comprehensive rehabilitation, de?ned as systematic multidisciplinary treat-ment given by physicians, occupation-al therapist, psychologist, bio-engineer and exercise physiologists. The reha-bilitation programmes included physi-cal therapy with exercise aiming at im-prove aerobic ?tness, muscle strength, mobility and balance, virtual real-ity rehabilitation, occupational therapy and self-management programmes. At discharge, subjects were instructed to maintain their habitual physical activ-ity and diet during the experimental period.

Exclusion criteria were age <18 years, RA functional class

Corticosteroids dosages were main-tained on <10 mg/day when possible and, in order to avoid any confound-ing factors, anti-in?ammatory drugs (NSAIDs) schedule was maintained as reported within 3 months before en-rollment (Cox-2 inhibitors about twice/ week). The treatment schedule was adapted when needed and any modi-?cations were recorded. Clinical and laboratory assessments were re-evalu-ated in all subjects at the end of the re-habilitative treatment (T1) and after 3 (T2), 6 (T3) and 9 (T4) months. Results

Because of intolerance to the exer-cise, 6 patients were excluded from the study, thus 32 subjects (mean age: 62.63±13.35 years; mean disease dura-tion: 14.87±6.37 years) concluded the 4-weeks rehabilitation programme. All subjects were receiving a second bio-

logic agent from a 16±3 months mean

period. More in detail, 2 subjects were

receiving etanercept, 3 adalimumab, 2

in?iximab plus methotrexate (15 mg/

week), 3 abatacept, 9 tocilizumab, 9

rituximab plus methotrexate (15 mg/

week), 6 golimumab plus methotrex-

ate (15 mg/week) and 6 certolizu-

mab. Among the study population, 7

(21.9%), 15 (46.9%) and 10 (31.3%)

resulted in II, III and IV FC respective-

ly. As shown in Table I, all the clinical

outcomes signi?cantly improved at the

different follow-up times as compared

to baseline, while a signi?cant ESR

reduction was found until T2. In par-

ticular, since T1, a signi?cant improve-

ment in function and fatigue indices

was found. Despite a slight worsening

of these values up to T4, the statistical

difference was maintained signi?cant

as compared to T0 (p always <0.001).

Of interest, as shown in Figure 1, also

DAS-28 improved during follow-up.

Stratifying according to age (over- or

under- 60 years of age), no signi?cant

differences in Δ% were found for all

clinical and laboratory outcomes at the

different follow up times (p always

>0.005). Of interest, at T4, the Δ%

FACIT directly correlated with Δ%

TJC and Δ% SJC (p<0.005). Moreover,

Pearson’s correlation showed that Δ%

FACIT at T1 directly correlated with

Δ%FACIT at T2, T3 and T4 (p always

<0.001). In addition, linear regression

analysis showed that Δ%FACIT at

T1 results predictor of Δ%FACIT at

T4 (β=0.883, p<0.001). A direct cor-

relation among disease duration and

Δ%ESR (r=0.455, p<0.001), Δ%DAS-Table I. Clinical and laboratory outcomes at different follow-up times.

T0 T1 T2 T3 T4

TJC 18.63 ± 3.4 11.84 ± 3 11.56 ± 3.07 11.88 ± 3.2 11.69 ± 3.47 SJC 13.13 ± 3.96 7.34 ± 2.44 6.84 ± 2.5 6.88 ± 2.55 6.94 ± 2.9 VES 29.66 ± 23.9 18.16 ± 14.4 19.84 ± 15.15 21.47 ± 15.97*21.38 ± 14.54* GH 29.44 ± 9.08 47 ± 8.7 50.38 ± 7.21 49.75 ± 7.14 48.39 ± 6.3 DAS-28 5.98 ± 0.5 5.20 ± 0.55 5.15 ± 0.87 5.21 ± 0.83 5.3 ± 0.69 HAQ 2.42 ± 0.43 2.13 ± 0.42 2.13 ± 0.42 2.18 ± 0.42 2.19 ± 0.38 FACIT 16.75 ± 9 33 ± 9.06 33.63 ± 11.75 32.53 ± 12.9 29.22 ± 10.52 p vs. T0 always <0.001. *p vs

. T0 >0.05.

Fig. 1.Trend of DAS-28 at different follow-up times.

28 (r=0.513, p<0.001) and Δ%HAQ (r=0.452; p<0.001) at T4 was found. Stratifying according to FC, no statisti-cal signi?cance was found in Δ% of all variables evaluated (p always >0.05). As to the secondary endpoint, at T4, the prevalence of DAS-28>5.1 resulted similar in the population strati?ed ac-cording to T0-T4 Δ%FACIT tertiles (1st tertile: 63.6%; 2nd tertile: 63.6%; 3th tertile: 50.0%; p for trend 0.767). No NSAIDs or corticosteroids modi?ca-tion was needed.

Discussion

Our ?ndings highlight the contribution of exercise in improving fatigue and ar-ticular function in female RA patients treated with biologics, who experienced an inadequate response to therapies even because of join damage. In order to avoid the inability to distinguish nat-urally occurring recovery from rehabil-itation effects we enrolled only patients treated with biologic DMARDs since at least 12 months, maintaining corti-costeroids and NSAIDs dosages stable during the study period. RA patients typically suffer from pain, reduced muscle strength and impaired physical function. Moreover, fatigue is common in this clinical setting being considered by patients a key determinant of their quality of life (7). Recent reports sug-gest that exercise should be carefully prescribed in these subjects (8). In ad-dition, evidence is lacking for the effec-tiveness of exercise in patients of FC III and IV (9). Accordingly, in our knowl-edge this is the ?rst study evaluating the effects of a rehabilitative programme in FC≥II subjects diagnosed with estab-lished RA undergoing biologics. It was initially thought that exercise might worsen the symptoms and cause addi-tional damage. However, more recent reports have shown that physical activ-ity plays a key role in RA (10). In line with these ?ndings, our results show a signi?cant improvement in all the vari-ables evaluated. In detail, as shown by HAQ and FACIT variations, function and fatigue signi?cantly improved in 4 weeks. FACIT at T1 directly related to Δ%FACIT at T2, T3 and T4. In addi-tion, Δ%FACIT at T1 has been found to be a predictor of Δ%FACIT at T4. These results support the hypothesis

that a greater functional recovery at

T1 will lead to a greater functional im-

provement over time. At T1 a reduction

of the percentage of subjects in high

disease activity was found. This result

was maintained up to T4, suggesting

a positive effect of rehabilitation on

disease activity. On the other hand, as

shown by stratifying according to age

and FC, older age and a severe func-

tional status did not affect the likeli-

hood of a good response to exercise. Of

interest, whereas Δ%FACIT correlates

with Δ%TJC and Δ%SJC, no correla-

tion was found with Δ%DAS-28. This

apparently contrasting result is likely to

be explained by the composite nature of

DAS-28. Indeed, at variance with TJC

and SJC, other parameters relevant to

de?ne the disease activity (ESR and pa-

tient’s global assessment of health) did

not correlate with Δ%FACIT.

These ?ndings suggest that fatigue

represents an independent RA clinical

feature which, regardless of disease ac-

tivity, should be investigated in all RA

subjects. The latter is widely discussed.

In particular, nowadays there is agree-

ment about the positive effect of train-

ing on RA symptoms (9), but there is no

evidence that exercise has detrimental

effects on disease activity (6, 9). Fur-

ther analyses of the impact of disease

activity show that fatigue is mainly as-

sociated with pain and that SJC and the

ESR have no signi?cant associations.

Accordingly, Huyser et al. found that

the best predictors of fatigue were pain

and depressive symptoms (11). In ad-

dition, less disease activity was asso-

ciated with greater fatigue. Other stud-

ies concluded that pain and depression

appear to be linked to higher fatigue

but not disease activity (12). These

differences could derive from the dif-

ferent clinical settings evaluated, such

as early and established RA. In our set-

ting, also ESR signi?cantly reduced to

T2. This is in line with previous reports

showing the attitude of physical activi-

ty in improving in?ammatory reactants

in RA (13). Moreover, circulating cy-

tokines re?ect disease activity and may

also play a role in the co-morbidities,

such as vascular involvement(14, 15)

and rheumatoid cachexia (13). Recent

reports assessed the effectiveness of

a systematic multidisciplinary treat-

ment in ameliorating fatigue, function

and pain in subjects affected by dif-

ferent joint and muscle diseases (16,

17). In particular, Carbonell-Baeza et

al.showed that a 3-month multidisci-

plinary intervention based on exercise

and psychological therapy is effective

in improving fatigue, stiffness, anxi-

ety, depression and quality of life in

women with ?bromyalgia (18). Other

groups evaluated the effectiveness of

a combined rehabilitation and pharma-

cological treatment in subjects with se-

vere osteoarthritis, founding that reha-

bilitation is effective in reducing pain,

especially by adding appropriate phar-

macological treatment(19) and that the

implementation of multidisciplinary

health care programmes is able to in-

crease patients’ satisfaction (20). Our

study reveals some potential limita-

tions such as the lack of a control group

and a relatively small sample size. Be-

ing a rehabilitative centre we could not

obtain a control group without training

and by enrolling only female subjects,

we tried to evaluate a homogeneous

sample. Of interest, these patients who

were affected by established disease

were different from those in many of

the fatigue clinical trials.

In conclusion, although many authors

agree on the importance of exercise

in RA, there is no speci?c therapy for

rheumatoid cachexia and its major fea-

tures. In this pilot study we showed

that in RA patients in FC ≥II undergo-

ing biologics, a personalised training

improves the RA features less respond-

ing to traditional therapies, fatigue and

function. Larger studies assessing the

drivers of fatigue in established RA are

needed.

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