Arthritis Care & Research Vol. 67, No. 10, October 2015, pp 1426–1439 DOI 10.1002/acr.22595 C 2015, American College of Rheumatology V

ORIGINAL ARTICLE

Effectiveness of Nonpharmacologic Interventions in Systemic Sclerosis: A Systematic Review LINDA M. WILLEMS,1 JOHANNA E. VRIEZEKOLK,1 ANNE A. SCHOUFFOER,2 JANET L. POOLE,3 € 5 LINDA KWAKKENBOS,6 TANJA A. STAMM,4 CARINA BOSTROM, 7 THEODORA P. M. VLIET VLIELAND, AND CORNELIA H. M. VAN DEN ENDE1

Objective. To systematically and comprehensively document the effectiveness of nonpharmacologic interventions on physical functioning and psychological well-being in patients with systemic sclerosis (SSc). Methods. Multiple electronic databases were searched for studies on the effectiveness of nonpharmacologic interventions in SSc. Randomized clinical trials (RCTs), controlled clinical trials (CCTs), and observational designs (ODs) with ‡10 participants were included. Two reviewers independently assessed methodologic quality using the Downs and Black checklist. Results. Twenty-three studies (9 RCTs, 4 CCTs, and 10 ODs) were included. Studies assessing comparable interventions were grouped, resulting in data for 16 different interventions. The total number of patients included per study ranged from 10 to 53. Seventeen different outcome domains were assessed, with hand function, limitations in activities, and quality of life being assessed most frequently. Three studies, all RCTs, were rated as high quality. These RCTs reported that 1) a multifaceted oral health intervention improves mouth hygiene, and additional orofacial exercises did not improve mouth opening, 2) a multidisciplinary team-care program improves limitations in activities, mouth opening, and hand grip strength, and 3) manual lymph drainage improves hand function, limitations in activities, and quality of life. Conclusion. The body of knowledge regarding nonpharmacologic care in SSc is very limited due to the wide variety in studied interventions and outcomes in the relatively uncommon but highly disabling disease. To structure and focus future research, an international consensus should be established to prioritize primary targets for nonpharmacologic treatment and the content of interventions and to agree on a core set of outcome measures.

INTRODUCTION Systemic sclerosis (SSc) is a rare and complex systemic autoimmune disease of unknown cause that affects the skin and multiple organs due to fibrosis (1). SSc is a clini-

Supported by the NVLE (National Association for Lupus, Antiphospholipid Syndrome, Scleroderma, and Mixed Connective Tissue Disease). 1 Linda M. Willems, MSc, Johanna E. Vriezekolk, PhD, Cornelia H. M. van den Ende, PT, PhD: Sint Maartenskliniek, Nijmegen, The Netherlands; 2Anne A. Schouffoer, PhD: Leiden University Medical Center, Leiden, and Haga Teaching Hospital, The Hague, The Netherlands; 3Janet L. Poole, PhD, OTR/L: University of New Mexico, Albuquerque; 4Tanja A. Stamm, PhD: Medical University of Vienna, Vienna, om, PhD: Karolinska Institutet, StockAustria; 5Carina Bostr€ holm, Sweden; 6Linda Kwakkenbos, PhD: Jewish General Hospital and McGill University, Montreal, Quebec, Canada; 7 Theodora P. M. Vliet Vlieland, MD, PhD: Leiden University Medical Center, Leiden, The Netherlands. Address correspondence to Linda M. Willems, MSc, Sint Maartenskliniek, PO Box 9011, 6500 GM Nijmegen, The Netherlands. E-mail: [email protected]. Submitted for publication October 8, 2014; accepted in revised form March 24, 2015.

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cally heterogeneous disease, since patients can experience a broad range of symptoms, such as fatigue, pain, impaired hand function, dry mouth, and sleeping difficulties (2–6). These symptoms are commonly associated with a considerable impact on the ability to carry out everyday activities (2,3), and the majority of patients report impairments in their physical as well as mental health–related quality of life (7–9). Comprehensive care in chronic diseases, including SSc, involves a combination of both pharmacologic and nonpharmacologic interventions (10). Because there is no cure, nonpharmacologic treatment, including psychological, educational, and rehabilitation interventions, may be provided as an adjunct to medical treatment in SSc. Nonpharmacologic care aims to attenuate disability and support patients in coping with the disease (11). Nonpharmacologic care can target a broad range of symptoms simultaneously, depending on the needs expressed by patients. To help guide medical care for patients with SSc, the European League Against Rheumatism (EULAR) and the EULAR Scleroderma Trials and Research group have developed evidence-based, consensus-derived recommendations for the pharmacologic treatment of SSc (12). The authors of these guidelines also emphasized the potential

Nonpharmacologic Care in SSc

Significance & Innovations  The body of knowledge regarding nonpharmacologic care in systemic sclerosis (SSc) is limited and fragmented.  In SSc research a wide variety exists in treatment targets, the content of nonpharmacologic interventions, and outcomes measures.  International consensus is needed to prioritize primary targets for nonpharmacologic treatment, the content of interventions, and a core set of outcome measures.

importance of psychosocial and rehabilitation interventions in disease management but could not make recommendations for or against these types of interventions. To contribute to developing such guidelines, an overview of the effectiveness of nonpharmacologic interventions in patients with SSc is needed. To date, 3 reviews have been published concerning nonpharmacologic care in SSc. Poole (13) reviewed the evidence for the efficacy of rehabilitation techniques for musculoskeletal impairments in persons with SSc; Casale et al (14) summarized the current management of skin, joints, tendons, muscles, pain, ergonomics, and working interventions in SSc; and Alantar et al (15) reviewed preventive and curative treatments for oral and dental involvement in patients with SSc. However, these reviews did not use a systematic approach to identify and synthesize evidence, did not assess the quality of included studies, and had a narrow scope of nonpharmacologic interventions and outcome measures to be included in the review. The objective of this study was, therefore, to systematically and comprehensively review the evidence on the effectiveness of nonpharmacologic interventions on physical functioning and psychological well-being in patients with SSc.

MATERIALS AND METHODS An expert panel consisting of 2 physical therapists (CHMvdE and CB), an epidemiologist (TPMVV), 2 occupational therapists (TAS and JLP), 3 psychologists (LK, JEV, and LMW), and a rheumatologist (AAS) developed the review protocol, including the eligibility criteria for studies to be included, the methods of selection of studies, assessment of methodologic quality, summarizing the evidence, and interpretation of the results. Search strategy. The databases MEDLINE, Embase, CINAHL, PsycINFO, Cochrane Library, and Web of Science were searched from 1990 to March 2014. The broad computerized search strategy consisted of the combination of 2 main components (for the detailed search strategy, see Supplementary Table 1, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/ acr.22595/abstract). First, the strategy identified studies

1427 involving patients with SSc, using the key words and free text words “systemic scleroderma,” “diffuse scleroderma,” “limited scleroderma,” “systemic sclerosis,” and “scleroderma.” Second, the search identified studies on nonpharmacologic interventions, including more than 50 search terms that reflected types of interventions (e.g., “rehabilitation,” “non-pharmacological treatment,” “physical therapy modalities,” “exercises,” “massage,” “stretching,” “behavior therapy,” “occupational therapy,” “splints,” “activities of daily living,” “nutrition therapy,” and “dental hygiene”). To ensure a broad search, no search terms for the identification of outcome measures or for study design were applied. The search strategy was formulated in MEDLINE and was adapted for use in the other databases. Additionally, the reference lists of relevant articles and review articles were hand searched for additional relevant studies. Inclusion criteria and procedure. Studies were eligible for inclusion in the review if 1) the study was published in English, German, French, Spanish, or Dutch, since these languages are mastered by the authors, and there was no budget available to consult translators, 2) the study was published in a full-length article or full written report, 3) the publication date was between 1990 and 2014, 4) the study sample consisted of patients ages $18 years with SSc, 5) outcomes for patients with SSc were reported separately in case of studies with a mixed patient sample, 6) the effectiveness was assessed of at least 1 nonpharmacologic intervention, defined as an intervention fitting in the domains of physical therapy, psychological therapy, occupational therapy, nursing, nutrition therapy, podiatry, and oral/dental hygiene therapy, excluding medication, surgery, or combined interventions with injections, 7) at least 1 outcome domain was assessed representing physical functioning or psychological well-being, and 8) at least 10 study participants were included. The procedure for inclusion of the studies was based on the recommendations of van Tulder et al (16). The first selection, based on titles and abstracts and in consideration of the inclusion criteria, was independently performed by 2 reviewers (LMW and JEV). If either deemed an article potentially eligible based on title/abstract review, then a full-text review was completed. The second step of inclusion was performed by the same 2 reviewers, who independently considered the criteria described above using full-text articles. Disagreements after full-text review were resolved by consensus. A third reviewer (CHMvdE) was consulted when agreement was not achieved. Quality assessment. To evaluate the quality of both randomized and nonrandomized studies, the Downs and Black checklist was used (17), consisting of 27 criteria representing 5 domains: study reporting, external validity, internal validity–bias, internal validity–confounding, and power. The Cochrane Musculoskeletal Group has rated the Downs and Black checklist in the top 6 quality assessment tools that are potentially useful for systematic reviews including nonrandomized studies (18–20). Item 27 of the checklist was slightly modified (see Supplemen-

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Willems et al

tary Table 2, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22595/ abstract) (21,22). For each study, a total quality score was computed by adding up all item scores, resulting in a maximum possible score of 28 (item 5, where 0 5 no, 1 5 partially, and 2 5 yes). The checklist does not provide a classification for distinguishing between low- and highquality studies. Consequently, we arbitrarily defined a priori that a study with a score $19 was considered of high quality, reflecting two-thirds of the maximum score. The methodologic quality of all included studies was assessed independently by 1 reviewer (LMW), and 2 reviewers each assessed half of the data set (JEV and CHMvdE). The 3 reviewers pilot tested the checklist for 3 studies that were not included in the current review. Disagreement was resolved by consensus. If consensus could not be reached, a third reviewer (CHMvdE or JEV) was consulted. The interrater reliability was examined using Cohen’s kappa. Statistical analysis. Data were extracted for intervention characteristics, patient characteristics, outcome measures, study methods, and study results. One reviewer (LMW) extracted the data and entered data items into a standardized spreadsheet. Performing a meta-analysis seemed inappropriate due to the heterogeneity of the included studies with regard to intervention content, mode of delivery, duration, and outcome measures. Considering the heterogeneity of outcome measures, we decided pragmatically to categorize the outcome measures in outcome domains on the basis of consensus among study authors CHMvdE, JEV, and LMW, and we sorted the domains according to the International Classification of Functioning, Disability, and Health. A list of 17 relevant outcome domains was compiled, including hand function/dexterity, Raynaud’s phenomenon, aerobic capacity, muscle strength, fatigue, pain, mood, skin problems (e.g., skin thickness, elasticity, and stiffness), mouth function, mouth hygiene, face function, gastrointestinal problems, limitations in activities, quality of life, cognitions, coping, and need for education. When outcome measures were related to a specific body part, the outcome domain was classified according to the localization. For example, hand pain and hand skin score were classified as hand function, rather than as pain or skin problems, respectively. For each outcome domain included in a study, the reported effect was scored as positive or negative when results were statistically significant, and no effect when results were not statistically significant. Results with a P value less than or equal to 0.05 were considered to be statistically significant. A number of decision rules were defined to score the effectiveness transparently. First, when multiple outcome measures and/or multiple subscales were used to assess the same outcome domain within a study, then .50% of the outcome measures or subscales used needed to be effective to score a positive. Second, when total scores were provided, those scores were preferred over the results of subscales scores. The authors of the high-quality studies were contacted to request additional data to calculate effect sizes and their 95% confidence intervals. Where possible, the effect size

Figure 1. Flow diagram of inclusion procedure.

was calculated using the difference between the means of the intervention and control group on the post measurement divided by the pooled SDs. A positive effect size indicated that the intervention was successful, whereas a negative effect size indicated that the control group had been superior. The values of the effect sizes were interpreted as small (0.20 # effect size ,0.50), medium (0.50 # effect size ,0.80), and large (effect size $0.80) (23).

RESULTS Search results. The electronic database search yielded 2,295 unique publications for screening of title and abstract, of which 36 articles were obtained for full-text review (Figure 1). Twenty-four articles, reporting on 23 studies, met the inclusion criteria. In 1 study the intervention of orofacial exercises was nested in a broader oral health intervention, and the results of these articles were considered together for the purpose of the present study (24,25). Characteristics of included studies. The characteristics of the included studies are shown in Table 1. Of these studies, 9 were randomized clinical trials (RCTs), 4 were controlled clinical trials (CCTs), and 10 were observational designs. Two CCTs included healthy controls, and in 1 CCT and 1 RCT the nontreated hand/arm of the patient served as control. The total number of participants included in the studies varied from 10 to 53, the average age ranged from 44 to 57 years, the percentage of women ranged from 65% to 100%, and the mean disease duration ranged from 5 to 11 years. The effectiveness of the following interventions was assessed: education (26), oral therapy (24,25,27,28), comprehensive rehabilitation program for physical and/or psychological functioning (29,30), self-management (31,32),

RCT

Yuen, 2011, US (24); Yuen, 2012, US (25)

OD

Oral therapy Poole, 2010, US (27)

OD

OD

Patient education Pai, 2010, Taiwan (26)

Pizzo, 2003, Italy (28)

Study design

First author, year, country (ref.)

6 months

2 days

Mouth stretching exercises for at least 18 weeks 15 min, twice a day and oral augmentation exercise with a stick of soft wood daily during 18 weeks. Multifaceted oral health intervention: 6 months; adaptive oral hygiene devices, subgroup instruction and demonstration on 6 months the use of the devices. Brush teeth for 2 min and floss twice a day for 6 months. Subgroup: orofacial exercises including manual mouthstretching and oral-augmentation exercises with a wooden stick (oral aperture ,40 mm), twice a day for 6 months.

Dental examination and cleaning by a dental hygienist. A structured home program consisting of patient education on brushing and flossing techniques, hand exercises 3 sets of 5 stretches once a day, facial exercises 5 stretches for 3–5 seconds once a day, individualized adapted dental appliances, and a 6month supply of dental products. Once or twice a day for 6 months.

Standardized nursing instruction about steroid pulse therapy both verbal and written, individualized to the patient. Minimum of 10 min each day for 2 days.

Post intervention assessment

Usual dental care

NA

NA

NA

Controls

26/22; subgroup 13/15

10/NA

17/NA

20/NA

No. patients†

52/49; subgroup 52/51

57

54

NR

Mean age, years†

81/77; subgroup 85/73

100

88

NR

Women, %†

8/7; subgroup 11/6

NR

11

NR

Mean disease duration, years†

L€ oe Silness gingival index; subgroup: maximal mouth opening

Maximal mouth opening

NR

NR

Primary outcome

Study design, description of the study interventions, patient characteristics, and outcome measures*

Intervention group

Table 1.

(continued)

Mouth hygiene (L€ oe Silness gingival index), subgroup: mouth function (maximum oral aperture)

Hand function (Keitel Function Test, grip strength, timed button test, grooved pegboard), mouth function (lip aperture, teeth aperture), mouth hygiene (patient hygiene performance index, xerostomia) Mouth function (maximal mouth opening)

Need for education (questionnaire need for nursing instruction)

Outcome domain (outcome measure)‡

Nonpharmacologic Care in SSc 1429

OD

RCT

Study design

Self-management Poole, 2013, US OD (31)

Kwakkenbos, 2011, The Netherlands (30)

Comprehensive rehabilitation for physical and/or psychological functioning Schouffoer, 2011, The Netherlands (29)

First author, year, country (ref.)

Mail-delivered self-management program, consisting of a workbook and face, mouth, hand, arm, and leg exercises on DVD. Participants were expected to complete the program in 3–4 months.

Psychoeducational group program with the following topics: goal setting and evaluation, education about the disease, education about joint protection and energy conservation, discussing psychosocial aspects of the disease, and education about benefits of exercise. Introductory lesson on Tai Chi was provided. Modules of 1.5 hours each, covering 13 different topics, scheduled over 3 weekends.

Multidisciplinary team-care program with individual treatment goals once a week for 12 weeks, including general exercises, hand/mouth exercises, and educational sessions. Individual supervised exercises provided by a local physical therapist and a home-based exercise program at least 6 days a week for 12 weeks.

Intervention group

4 to 6 weeks after program completion

6 weeks

12 weeks

Post intervention assessment

Usual care

NA

NA

49/NA

41/NA

28/25

No. patients†

(Cont’d)

Controls

Table 1.

54

53

54/52

Mean age, years†

92

83

68/84

Women, %†

7

10

7/8§

Mean disease duration, years†

NR

NR

NR

Primary outcome

(continued)

Coping (ASES), fatigue (MAF), hand function (SFAQ), limitations in activities (HAQ), mood (CES-D), pain (VAS)

Aerobic capacity (VO2 max), fatigue (CIS-20), hand function (HAMIS, grip strength), limitations in activities (6-minute walking test, SHAQ), mouth function (maximal mouth opening), pain (VAS pain), quality of life (SF36) Cognitions (ICQ acceptance, ICQ helplessness, ALS), coping (UCL), fatigue (VAS fatigue), limitations in activities (HAQ DI), mood (IRGL depressed mood), pain (VAS pain)

Outcome domain (outcome measure)‡

1430 Willems et al

Study design

Maddali Bongi, 2009, Italy (34)

RCT

Comprehensive rehabilitation for hands and/or face Antonioli, CCT 2009, Italy (33)

Poole, 2014, US OD (32)

First author, year, country (ref.)

Rehabilitation program for hands and face. Hand involvement was treated with a combination of connective tissue massage and Mc Mennell joint manipulation. Manual lymph drainage if patients had edematous hands. Face involvement was treated with a combination of Kabat’s method, connective tissue massage, and kinesitherapy. Hydrokinesitherapy (for patients without ulcers) or land-based rehabilitation (for patients with ulcers), and respiratory rehabilitation exercises. One or 2 sessions per week for 9 weeks.

Rehabilitation program consisted of warm-up and cool-down exercises, training of motor functions, diaphragmatic breathing, controlled coughing exercises, treadmill, free walking, finger stretching, and occupational therapy for 2 weeks, daily 30-min sessions (10 sessions in total). Physiotherapy was prescribed when necessary. At-home exercise program was prescribed on days when the program was terminated.

Interactive internet-based selfmanagement program. The program consisted of 10 modules (e.g., self-advocacy, fatigue and energy conservation, coping and body image/appearance), an exercise video, learning activities, worksheets, and resources. Participants proceeded through the modules at their own pace over 10 weeks.

Intervention group

9 weeks

2 months

10 weeks

Post intervention assessment

Continue current care

Usual care

NA

10/10

16/17

16/NA

No. patients†

(Cont’d)

Controls

Table 1.

58/56

67/57§

52

Mean age, years†

60/70

100/94

88

Women, %†

9/9

15/9§

8

Mean disease duration, years†

NR

NR

NR

Primary outcome

(continued)

Aerobic capacity (modified Borg Dyspnoea Scale, VAS dyspnoea, lung function test: FVC and DLCO), hand function (HAMIS), limitations in activities (HAQ DI, 6-minute walking test), quality of life (SF-36, Saint George’s Respiratory Questionnaire), skin problems (MRSS) Face function (VAS face), hand function (HAMIS, Duruoz scale, hand opening, fist closure, water volumetric test), limitations in activities (HAQ DI), mouth function (mouth opening), quality of life (SF- 36)

Cognitions (PAM), coping (SE, heiQ), fatigue (VAS fatigue), limitations in activities (HAQ DI), mood (CESD), pain (VAS pain), quality of life (self-rated health)

Outcome domain (outcome measure)‡

Nonpharmacologic Care in SSc 1431

OD

OD

Stretching Mugii, 2006, Japan (38)

RCT

Maddali Bongi, 2010, Italy (36)

Aerobic training Pinto, 2011, Brazil (37)

RCT

Study design

Maddali Bongi, 2009, Italy (35)

First author, year, country (ref.)

Home program self-administered exercises for finger stretching (3–10 repetitions, each stretch held 10 seconds). Daily for 1 year.

Supervised concurrent training session consisted of treadmill warm-up (5 min) followed by resistance training (30 min), treadmill aerobic training (20 min), and stretching exercises (5 min). Resistance training included 5 exercises for the main muscle groups: bench press, leg press, lat pulldown, leg extension, and seated row. 1-hour sessions, twice a week for 12 weeks.

Rehabilitation program for the face with a combined 4-step procedure of connective tissue massage (10 min), Kabat’s method (15 min), kinesitherapy (15 min), relaxing exercise (20 min). In total, 1 hour, twice a week for 9 weeks. A home program of mimic exercises daily for 18 weeks.

Combined rehabilitation treatment of connective tissue massage and Mc Mennell joint manipulation for1 hour, twice a week for 9 weeks. Home exercise program for the hands daily, 20 min for 9 weeks.

Intervention group

1 year

12 weeks

18 weeks

9 weeks

Post intervention assessment

NA

NA

Home program of mimic exercises only

Home exercise program for the hands daily 20 min for 9 weeks

45/NA

11/NA

20/20

20/20

No. patients†

(Cont’d)

Controls

Table 1.

49

44

57/57

56/58

Mean age, years†

87

100

90/80

80/70

Women, %†

5

7

10/9

9/9

Mean disease duration, years†

NR

NR

NR

NR

Primary outcome

(continued)

Hand function (finger passive ROM test, hand skin score), limitations in activities (HAQ DI), skin problems (MRSS)

Aerobic capacity (VO2 peak, AT, RCP, heart rate rest, heart rate peak exercise), hand function (hand grip), muscle strength (leg press, bench press, low back strength, timed up and go, timed stands)

Hand function (HAMIS, Cochin hand functional disability scale, hand opening, fist closure), limitations in activities (HAQ DI), quality of life (SF-36) Limitations in activities (HAQ DI), mouth function (MHISS, mouth opening), quality of life (SF36), skin problems (MRSS)

Outcome domain (outcome measure)‡

1432 Willems et al

OD

RCT

Manual lymph drainage Maddali Bongi, 2011, Italy (42)

Ultrasound Uhlemann, 1990, Germany (43)

CCT#

RCT

RCT¶

Study design

Carbon dioxide baths Werner, 1996, Germany (41)

Pils, 1991, Austria (40)

Paraffin treatment Sandqvist, 2004, Sweden (39)

First author, year, country (ref.)

Ultrasound therapy of the hands with an intensity of 0.6 W/cm2, 6 min per region, 3 times a day for 6 days.

Manual lymph drainage of the hands. One session a week lasting 1 hour for 5 weeks.

Carbon dioxide baths.

Randomly selected hand treated with paraffin bath once a day. Immediately after the paraffin bath treatment, hand exercises were performed (isolated finger flexion, finger extension, finger abduction, and thumb abduction). Daily for 1 month. Paraffin wax treatments once a day for 3 months.

Intervention group

6 days

5 weeks

NR

3 months

1 month

Post intervention assessment

NA

Waiting list

Healthy controls received the same treatment as the intervention group

Paraffin wax treatments once a day for 12 days

Other hand treated with hand exercises only

24/NA

20/15

18/16

8/8

17/17

No. patients†

(Cont’d)

Controls

Table 1.

88

Women, %†

NR

57/57

46/NR

75

100/100

61/NR

Overall: 54 Overall: 69

53§

Mean age, years†

NR

8/8

NR

NR

6§

Mean disease duration, years†

NR

NR

NR

NR

NR

Primary outcome

(continued)

Hand function (hand strength)

Hand function (water volumetric test, HAMIS, VAS hand edema, VAS hand pain), limitations in activities (HAQ, VAS interference edema, VAS interference pain), quality of life (SF36)

Skin problems (microcirculation of skin)

Hand function (grip strength, palmar pinch, flexion/ mobility, maximal abduction, hand skin induration)

Hand function (ROM, HAMIS, grip force), pain (VAS pain), skin problems (VAS stiffness, VAS skin elasticity)

Outcome domain (outcome measure)‡

Nonpharmacologic Care in SSc 1433

Study design

OD

Home total parenteral nutrition as long as required.

Home use transcutaneous electrical nerve stimulation (TENS) application on 2 GI acupoints (ST36 Zusanli and PC6 Neiguan) after an instruction session, 30 min, twice a day for 2 weeks.

12 months

2 weeks

4 weeks

4 weeks

7 days after treatment

NA

Healthy controls received only 1 30-min session with TENS

Waiting list

Waiting list

Other arm no treatment

Controls

12/NA

17/9

10/10

8/10

30/30

No. patients†

(Cont’d)

49

57/35

53/59

50/59

56

Mean age, years†

75

82/33

80/90

88/90

97

Women, %†

NR

NR/NA

4/2§

6/2§

7

Mean disease duration, years†

NR

NR

Scleroderma VAS for RP

Scleroderma VAS for RP

NR

Primary outcome

Gastrointestinal (BMI, weight)

Aerobic capacity (sympathovagal balance), gastrointestinal (GI questionnaire), quality of life (SF36)

Raynaud’s phenomenon (scleroderma VAS RP)

Raynaud’s phenomenon (scleroderma VAS RP)

Skin problems (MRSS, VAS skin wellness, skin thickness, skin vascularity)

Outcome domain (outcome measure)‡

* OD 5 observational design; min 5 minute; NA 5 not applicable; NR 5 not reported; RCT 5 randomized controlled trial; VO2 5 oxygen uptake; CIS-20 5 Checklist Individual Strength 20; HAMIS 5 Hand Mobility in Scleroderma test; SHAQ 5 Scleroderma Health Assessment Questionnaire; VAS 5 visual analog scale; SF-36 5 Short Form 36 health survey; ICQ 5 Illness Cognition Questionnaire; ALS 5 Acceptance Limitations Scale; UCL 5 Utrechtse Coping List; HAQ DI 5 Health Assessment Questionnaire disability index; IRGL 5 Impact of Rheumatic Diseases on General Health and Lifestyle; ASES 5 Arthritis Self-Efficacy Scale; MAF 5 Multidimensional Assessment of Fatigue; SFAQ 5 Scleroderma Functional Assessment Questionnaire; CES-D 5 Center for Epidemiologic Studies Depression Scale; PAM 5 Patient Activation Measure; SE 5 Chronic Disease Self-Efficacy; heiQ 5 Health Education Impact Questionnaire; CCT 5 controlled clinical trial; FVC 5 forced vital capacity; DLCO 5 diffusing capacity for carbon monoxide; MRSS 5 modified Rodnan skin thickness score; MHISS 5 Mouth Handicap in Systemic Sclerosis questionnaire; lat 5 latissimus dorsi; AT 5 anaerobic threshold; RCP 5 respiratory compensation point; ROM 5 range of motion; W/cm2 5 Watts per square centimeter; mJ/mm2 5 megajoules per square meter; Hz 5 hertz; RP 5 Raynaud’s phenomenon; GI 5 gastrointestinal; BMI 5 body mass index. † Values are either no. study subjects or no. treatment group/control group. ‡ Outcome measures are reported when a P value was provided in the results section. § Median rather than mean. ¶ Other hand/arm considered as control. # Healthy controls.

Home total parenteral nutrition Jawa, 2012, Canada (47)

CCT#

Deep oscillation (5–200 Hz) 3 times a week for 4 weeks.

Deep oscillation Sporbeck, 2012, RCT Germany (45)

Transcutaneous electrical nerve stimulation Sallam, 2007, US (46)

Biofeedback (5–200 Hz) 3 times a week for 4 weeks.

Extracorporeal shock wave therapy of the arm and hand of 1 arm consisting of 3 sittings. Defocused energy applied was 0.20–0.25 mJ/mm2.

Intervention group

Biofeedback Sporbeck, 2012, RCT Germany (45)

Extracorporeal shock wave therapy Tinazzi, 2011, CCT¶ Italy (44)

First author, year, country (ref.)

Post intervention assessment

Table 1.

1434 Willems et al

1, 2, 3, 4, 5, 6, 7, 8, 9, 10 1, 2, 3, 4, 5, 6, 9, 10 1, 2, 3, 4, 5, 6, 7, 9 1, 2, 4, 5, 6, 7, 9, 10 1, 2, 4, 5, 6, 7, 8, 9, 10 2, 3, 4, 5, 6, 7, 9 1, 2, 3, 4, 6, 7, 8, 9, 10 1, 2, 3, 6, 7, 9, 10 1, 2, 4, 6, 7, 9 1, 2, 4, 6, 7, 9, 10 1, 2, 3, 5, 7, 9 1, 2, 5, 6, 10 1, 3, 6, 7, 9, 10 2, 4, 5, 6, 7, 9 2, 3, 5, 6, 7, 8, 9, 10 1, 2, 4, 6, 7, 9 1, 2, 6, 7, 9, 10 1, 2, 3, 4, 6, 7, 9 1, 2, 3, 4, 6, 7, 9, 10 1, 2, 4, 7, 10 1, 4, 9 7, 10 1, 2, 9

Schouffoer (29)‡ Yuen (24,25)‡ Maddali Bongi (42)‡ Maddali Bongi (35) Pizzo (28) Maddali Bongi (36) Pinto (37) Antoniolo (33) Mugii (38) Kwakkenbos (30) Sandqvist (39) Sporbeck (45) Jawa (47) Maddali Bongi (34) Poole (31) Tinazzi (44) Pai (26) Poole (27) Poole (32) Sallam (46) Uhlemann (43) Pils (40) Werner (41) 13

13

13 13 13

11, 12, 13 11, 12 13 13 13 13 11, 13 11, 12 13 13 13

External validity 15, 16, 17, 18, 19, 20 15, 16, 17, 18, 19, 20 15, 16, 17, 18, 20 16, 17, 18, 20 16, 17, 18, 19, 20 16, 17, 18, 20 16, 17, 18, 20 16, 17, 18, 20 16, 17, 18, 20 16, 17, 18, 20 16, 17, 20 16, 17, 18, 20 17, 18, 19, 20 16, 20 16, 17, 20 16, 17, 18, 19, 20 16, 17, 18 16, 17, 18, 20 16, 17, 20 16, 18, 19 16, 17, 19 16, 17, 18 16

Internal validity, bias

26

26

21, 22, 23, 25, 26 21, 23, 24, 25, 26 21, 23, 25, 26 21, 23, 25, 26 22, 26 21, 23, 25, 26 26 21, 26 21, 22, 25, 26 22, 26 21, 22, 23, 26 22, 23, 24, 25 22, 26 21, 23, 25, 26 26 22, 26 26 26

Internal validity, confounding

Results of quality assessment using Downs and Black checklist*

27

27

27

Power

25 21 19 17 17 16 16 15 15 14 14 14 13 13 13 13 12 12 12 8 7 5 5

Quality score†

* Only the numbers for fulfilled criteria are reported. For detailed information about item methodologic quality, see Supplementary Table 2, available in the online version of this article at http:// onlinelibrary.wiley.com/doi/10.1002/acr.22595/abstract. ref. 5 reference. † Quality score is the sum of positive scores. ‡ Studies of high quality (quality score $19).

Study reporting

First author (ref.)

Table 2.

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Table 3. Outcome domains and outcome measures Hand function HAMIS HAMIS right hand HAMIS left hand Grip strength Water volumetric test VAS hand edema VAS hand pain Aerobic capacity VO2 max Fatigue CIS-20 Pain VAS pain Mouth function Maximal mouth opening Mouth hygiene Lo€e Silness gingival index Limitations in activities 6-minute walking test HAQ VAS interference edema VAS interference pain Quality of life SF-36 PCS SF-36 MCS

Between-group results of 3 high-quality RCTs evaluating effectiveness of nonpharmacologic intervention in systemic sclerosis* Yuen (24,25)†

Schouffoer (29)‡

Maddali Bongi (42)

0.48 (20.14, 1.07) 0.99 (0.26, 1.67)§ 1.09 (0.35, 1.77)§ 1.08 (0.42, 1.70)§ 0.70 (20.01, 1.37) 2.31 (1.41, 3.11)§ 1.01 (0.28, 1.70)§ 0.41 (20.19, 1.00) 0.27 (20.36, 0.90) 0.56 (20.10, 1.20) 0.46 (20.43, 1.31)

0.73 (0.12, 1.31)§

1.54 (0.79, 2.22)§ 0.75 (0.14, 1.35)§ 0.89 (0.22, 1.52)§

0.33 (20.31, 0.95) 20.08 (20.71, 0.55)

0.81 (0.10, 1.49)§ 1.07 (0.34, 1.76)§ 0.90 (0.18, 1.58)§ 0.74 (0.03, 1.41)§ 0.85 (0.13, 1.53)§

* All values are effect size (95% confidence interval). RCT 5 randomized controlled trial; HAMIS 5 Hand Mobility in Scleroderma; VAS 5 visual analog scale; VO2 5 oxygen uptake; CIS-20 5 Checklist Individual Strength 20; HAQ 5 Health Assessment Questionnaire; SF-36 5 Short Form 36 health survey; PCS 5 physical component summary; MCS 5 mental component summary. † Both references cite the same study. ‡ Effect sizes calculated with change scores. § P # 0.05.

comprehensive rehabilitation for the hands and/or face (33–36), aerobic training (37), stretching (38), paraffin treatment (39,40), carbon dioxide baths (41), manual lymph drainage (42), ultrasound (43), extracorporeal shock wave therapy (44), biofeedback (45), deep oscillation (45), transcutaneous electrical nerve stimulation (46), and home total parenteral nutrition (47). The most frequently examined interventions were aimed (among other treatment targets) to improve hand function (33–35,38–40,42–45) and the function of the mouth and face (24,25,27,28,34,36). The intervention duration ranged from 2 days (26) to 1 year (38). Of the included studies, 9 were home-based interventions (24,25,28,31,32,38–40,46,47), 5 were clinic/hospital– based interventions (26,30,34,37,42), 5 were combined home/hospital–based interventions (27,29,33,35,36), and 4 studies did not report the setting of the intervention (41,43–45). A primary outcome measure for the intervention was specified in 3 studies (13%). In addition, a variety of outcome measures were used across studies to assess a specific outcome domain. For instance, the outcome domain “hand function” was assessed in total by 18 different performance-based and self-reported outcome measures across the selected reports.

Methodologic quality. Initially, there was disagreement on quality ratings between the reviewers for 116 (19%) of the 621 (23 x 27) items scored. The interrater reliability of the methodologic quality assessment was 82.1% with Cohen’s k 5 0.64 for JEV and LMW, and 80.4% with Cohen’s k 5 0.61 for CHMvdE and LMW, both indicating substantial agreement (48). Three studies, all RCTs, met the predefined score for high quality (Table 2) (24,25,29,42). At least half of the study-reporting items were met in 87% of the studies (n 5 20), with item 8, relating reporting of important adverse events, being scored less frequently (n 5 4). Regarding external validity, both criteria on the representativeness of the study sample were met in 3 studies. Item 14, relating to the blinding of study subjects and reflecting internal validity bias, was not met by a single study, and item 15, relating to the blinding of assessors, was met by 3 studies. The criteria for assignment concealment and power calculation were met in 2 and 3 studies, respectively. Effectiveness of nonpharmacologic interventions. The effect sizes for the 3 studies that met criteria for high quality are shown in Table 3 and are discussed below. Detailed information about reported treatment effects of all the

Nonpharmacologic Care in SSc included studies is only shown in Supplementary Tables 3 and 4 (available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22595/abstract), because the heterogeneity of the interventions and outcome domains does not allow meaningful summarizing of the results across studies. The 3 high-quality RCTs investigated 4 different nonpharmacologic interventions. Yuen et al (24) reported that a multifaceted oral health intervention had a large positive effect on mouth hygiene after 6 months compared with dental care as usual (Table 3). However, orofacial exercises for those with an oral aperture size of less than 40 mm had no statistically significant effect on maximal mouth opening after 6 months compared with the no-exercise group (25). Schouffoer et al (29) reported that a 12-week multidisciplinary team-care program compared to usual outpatient care resulted in medium to large significant positive effects in limitations in activities, measured with the 6minute walking test and the Scleroderma Health Assessment Questionnaire, medium effects on maximal mouth opening, and large effects on grip strength. Maddali Bongi et al (42) reported that the experimental treatment of 1-hour manual lymph drainage for 5 weeks was superior to the waiting-list group and significantly improved hand function with medium to large effects (hand volume, the Hand Mobility in Scleroderma test, visual analog scale [VAS] hand edema, and VAS hand pain). Large effects were also observed for limitations in activities measured with the Health Assessment Questionnaire, VAS interference edema, and VAS interference hand pain. Furthermore, medium to large effects for quality of life measured with the Short Form 36 physical component summary score and the Short Form 36 mental component summary score were observed.

DISCUSSION Our study is the first that comprehensively and systematically documented the effectiveness of nonpharmacologic interventions in patients with SSc. Twenty-three studies were identified, but the wide variations in the content of interventions and outcome measures prevented a meaningful synthesis of results across studies. Three studies, all RCTs, met criteria for methodologic high quality. These RCTs reported that a multifaceted oral health intervention is effective in improving mouth hygiene and that orofacial exercises are not effective in improving maximal mouth opening (24,25), that a multidisciplinary team-care program is effective in improving limitations in activities, maximal mouth opening, and hand grip strength (29), and that manual lymph drainage is effective in improving hand function, limitations in activities, and quality of life (42). Findings should be interpreted with caution, however, given that only a single RCT was conducted for each intervention, each had a small sample size, and there was a lack of predefined primary outcome measures. Besides the heterogeneity in interventions and outcome measures, the low methodologic quality and the small sample sizes impeded summarization of results. Most studies were lacking external validity and internal validi-

1437 ty with regard to adjustment for confounding, randomization, and allocation concealment. In addition, the study with the largest sample size included only 53 participants in total, with 25 participants in the smallest group, which is even fewer than the recommended lower limit of 35 participants in the smallest group for inclusion of trials in meta-analyses (49,50). An important barrier to conducting adequately powered RCTs of nonpharmacologic interventions in SSc is the small number of people with the disease at any single center. International collaborations should be established, therefore, to overcome this barrier and to conduct well-designed and sufficiently large RCTs to facilitate the establishment of evidence-based recommendations for nonpharmacologic interventions. As the majority of patients with SSc experience a broad range of symptoms (2,3,51) that could be targeted by nonpharmacologic treatment, it is not surprising that singlecomponent interventions focusing on 1 symptom such as improving hand function, as well as multimodal interventions targeting a range of symptoms, were represented in the review. This variation could also explain why only 3 of 23 studies included in our review defined a primary outcome measure. Defining a primary outcome measure a priori is highly recommended (52,53) as a way to reduce the influence of reporting biases on the evidence base, and failing to do so hampers conclusions that can be drawn about the effectiveness of an intervention (54). However, defining a single primary outcome measure for multimodal interventions, targeting multiple symptoms simultaneously, is a challenge. To tackle this problem, a possible solution might be to use a patient-specific outcome as the primary outcome, such as the patient-specific symptoms questionnaire (55). Another solution might be to provide a combined score of different outcome domains that are targeted in an intervention, similar to the Outcome Measures in Rheumatology–Osteoarthritis Research Society International Response Criteria (56). For example, Hoogeboom et al (57) defined adapted responder criteria for their nonpharmacologic intervention and considered patients as responders if at least 3 of the 6 targeted areas (i.e., physical functioning, pain, fatigue, physical activity, acceptance, and patient global assessment) improved $20%. The results of our review do not allow the formulation of evidence-based recommendations for nonpharmacologic care in SSc. Considering the high clinical burden of SSc, however, an international research agenda is warranted to prioritize and focus future research. This research agenda should be based on an international consensus on a limited number of clearly defined nonpharmacologic interventions and outcome measures. Symptoms that are commonly experienced by patients with SSc and have a major impact on carrying out everyday activities, like fatigue, pain, limitations in hand function, and decreased mobility (2,3), need to be considered as primary targets for interventions. In addition, the characteristics and results of studies documented in this review could be a starting point to initiate discussion among international experts on the optimal content of interventions. In conclusion, the strength of evidence on the effectiveness of nonpharmacologic interventions in SSc is limited due to the great variety in interventions and the low meth-

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odologic quality of studies in this area. To increase the body of knowledge, international collaboration following an international research agenda is needed. To focus future research on the effectiveness of nonpharmacologic care for SSc, an international consensus on a limited number of treatment targets, interventions, and outcome measures is warranted.

AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Ms Willems had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Willems, Schouffoer, Poole, Stamm, Bostr€ om, Kwakkenbos, Vliet Vlieland, van den Ende. Acquisition of data. Willems, Vriezekolk. Analysis and interpretation of data. Willems, Vriezekolk, Schouffoer, Bostr€ om, Kwakkenbos, Vliet Vlieland, van den Ende.

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18.

19.

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