Assessment of skin, joint, tendon and muscle involvement

A. Akesson1, G. Fiori2, T. Krieg3, F.H.J. van den Hoogen4, J.R. Seibold5

1Lund University Hospital, Lund, Sweden; ABSTRACT The extent of skin involvement is also 2Istituto di Clinica Medica IV, Florence, This rep o rt makes re c o m m e n d at i o n s the prime clinical criterion for the sub- Italy; 3University of Cologne, Koln, for standardized techniques of data ga - classification of SSc into its two princi- 4 Germany; University Medical Centre t h e ring and collection rega rd i n g : 1 ) pal subsets Ð SSc with diffuse cuta- St. Raboud, Nijmegen, The Netherlands; 5UMDNJ Program, skin involvement 2) joint and tendon in - neous involvement (diffuse scleroder- New Brunswick, New Jersey, USA. volvement, and 3) involvement of the ma) and SSc with limited cutaneous Anita Akesson, MD, PhD; Ginevra Fiori, skeletal muscles. The recommendations i nvo l vement (limited scl e ro d e rma Ð MD; Thomas Krieg, MD; Frank H.J. van in this report derive from a critical re - p rev i o u s ly termed the “CREST syn- den Hoogen, MD, PhD; James R. Seibold, v i ew of the ava i l able literat u re and drome”) (3). By consensus and conven- MD. group discussion. Committee re c o m - t i o n , p atients with skin invo l ve m e n t Please address correspondence to: mendations are considered appropriate restricted to sites distal to the elbows James R. Seibold, MD, Professor and for descri p t ive clinical inve s t i gat i o n , and knees, exclusive of the face, are Director, UMDNJ Scleroderma Program, translational studies and as standards considered to have limited scleroderma MEB 556 51 French Street, New for clinical practice. whereas patients with involvement of Brunswick, New Jersey 08903-0019, USA. Skin invo l vement should be assessed sites proximal to the elbows and knees E-mail: [email protected] using the modified Rodnan skin score. and inclusive of the chest and abdomen Clin Exp Rheumatol 2003; 21 (Suppl. 29): Joint involvement, when symmetric sy - are said to have diffuse scleroderma. S5-S8. n ovitis is pre s e n t , could be best as - Some investigato r s hold that an interme - © Copyright CLINICAL AND sessed by the DAS-28 as is utilized in di a te syndrom e ex i s t s , wh i ch is des- EXPERIMENTAL 2003. r h e u m atoid art h ritis. Clinical assess - c ribed as skin invo l vement invo l v i n g Key words: Scleroderma, Rodnan ment should include a routinized evalu - the upper arms and thighs but sparing skin score, tender rubs, DAS-28. ation for the presence and number of the chest and abdomen (4, 5). palpable tendon friction rubs. Muscle This subclassification of SSc is closely involvement should be screened for by related to the time of onset, pace of performance of the serum creatine pho - development, and patterns of internal sphokinase assay and assessment of organ involvement and is accordingly proximal weakness. More specific test - strongly linked to survival. All descrip- ing including EMG, ma gnetic res o n a n c e tive clinical investigations in SSc today imaging and muscle biopsy should be should re q u i re the perfo rmance of a employed in those patients with clini - clinical assessment of the extent of skin cally significant only. involvement.

Skin involvement Severity of change Tightening and thickening of the skin Severity of skin involvement is highly (scleroderma) is a cardinal clinical fea- relevant to the study of individuals with ture of systemic sclerosis (SSc). There diffuse scleroderma. Consensus obser- are rare patients with characteristic se- vations by veteran observers hold that rologic, vascular and visceral features skin ch a n ge in diffuse scl e ro d e rm a of SSc who lack skin thickening (sys- evolves in three sequential stages: 1) temic sclerosis sine scleroderma) and early progression, 2) plateau or stabi- t h e re are many other disord e rs only lization, and 3) late improvement (1, 3, superficially related to SSc in which 6 , 7). Early progre s s ive skin ch a n ge s skin thickening is a cardinal cl i n i c a l appear to correlate with both tissue and feature (1), as for example, scleredema systemic immune activation and in- adultorum or eosinophilic . flammatory changes (1). The stabiliza- tion of skin involvement is associated Extent of change with evidence of reduced local and sys- The extent of skin involvement is the temic infl a m m ation. Later improve- single major criterion for the classifica- ment of skin involvement is thought to tion of SSc in comparison to other reflect an admixture of post-inflamma- major disorders (2). tory and post-fibrotic atrophy as well as

S-5 Skin, joint, tendon and muscle involvement in SSc / A. Akesson et al. the remodeling of previously fibrosed the local skin score should be recorded b reasts. The chest should be as- tissue. as 0. If the local skin is so tethered as to sessed with the subject in a sitting A variety of techniques have been inve- p re clude confident assessment, t h e position. stigated to estimate the degree of skin examiner should use his/her best judg- 6. Abdomen: Assess from the xiphoid thickening and/or tethering in discrete ment. to the pelvic brim. The ab d o m e n anatomic areas (6). The most widely Patients in whom areas of atrophic skin should be assessed with the subject used technique is the modified Rodnan (tethered, but not thickened) predomi- supine. skin score (mRSS) in which 17 body n ate are not considered ap p ro p ri at e 7. Thighs and Legs : Assess with the areas are examined by clinical palpa- choices for clinical trial participation su b ject lying down with the hips, tion and scored based on examiner jud- even if they might otherwise fulfill the knees and ankles comfort a bly fle xed . gement of skin thickness on a 4-point criteria for inclusion and not those for 8. Feet: Assess the dorsum only. Feet ordinal scale (0 = normal thickness; 1 = exclusion. should be examined with the subject mild thickening; 2 = moderate thicken- Experience has demonstrated that indi- lying down with the hips, k n e e s , ing; and 3 = severe thickening). The vidual investigators, while consistent, and ankles comfortably flexed. range of the mRSS is thus from 0 (no d i ffer in their rep o rting of the skin skin thickening) to 51 (grade 3 change score. Some are “maximizers” and as- Critique of the Modified Rodnan in all 17 body areas) (6-8). The areas sign scores to individual anat o m i c Skin Score examined in the mRSS scheme include areas according to the most severe local The mRSS is regarded as a measure of the right and left fingers, hands, fore- involvement. Others tend to “average” the degree of fibrosis, yet it does not a rm s , upper arm s , t h i g h s , l ower leg s skin involvement over a given surface discriminate between the contributions and feet, as well as the face, anterior area. For the purposes of multicenter to skin thickening of fibrosis, edema chest and abdomen. trials, investigators should be encour- and infl a m m ation. Ignoring the ele- The modified Rodnan skin score is rec- aged to score individual areas with a ment of tethering of the skin to deeper ommended as the core assessment score that is most representative at the structures can be seen as underestimat- technique for all international descrip- area under examination. For example, ing the total burden of skin involve- tive clinical investigations in SSc.The if the distal forearm has a patch consid- ment on the function and mobility of reasons for selection of the mRSS are ered 2+ whereas the remainder of the patients in the later atrophic stages of numerous and compelling. forearm is 1+, then 1+ would be the disease (9). most representative score. Alternative- There is controversy within the inves- Performance of the modified Rodnan ly, if the area rated 2+ was relatively tigative community as to the robustness Skin Score extensive, then 2+ would be the recom- of mRSS as a primary outcome mea- The mRSS can be easily taught and yet mended score for the forearm. sure. It is recognized that worsening its broad use in clinical settings outside Recommendations for patient position- skin scores are associated with a higher of the core of investigators who active- ing and assessment of the individual risk of renal invo l vement and deat h ly participate in trials has been limited. areas of examination are as follows: (10-12) and that improving the skin While inve s t i gator training sessions 1. Face: Assess the area between the score is associated with better function- have validated the utility of mRSS, the zygomatic arch and the lower man- al capacity and surv ival (13). Th e s e fo l l owing practical guidelines have dible. Do not assess the forehead. data argue that the mRSS is a surrogate evolved that enhance the understanding 2. Fingers: Concentrate on the skin of but perhaps not a primary measure of and application of the measure. We be- the dorsum of the fingers. Do not outcome. Nevertheless, the mRSS or a lieve that adherence to this methodolo- assess the palmar aspect. Skin distal similar technique remains a cru c i a l gy of mRSS will improve both the ac- to the DIP joints is difficult to parameter in determining whether an curacy and the measurement of sensiti- judge. If the area distal to the PIP SSc patient is the same, better or worse. vity to change. joints is ex c e s s ive ly tethered and The mRSS is a measure of skin thick- inevaluable, score the area between Other measures and future directions ening and not of skin tethering. Clini- the PIP and MCP joints only. Other ap p ro a ches are under study cians and investigators should not at- 3. H a n d s : Assess the dorsum of the which include techniques to objectively tempt to assess the potential contribu- hands only. The area is defined as assess skin thickness (durometer) (14); tions of edema, tethering, the skin between the MCP joints skin tethering (elastometer) (15); and and fibrosis as they assign regional skin and the wrists. to assess the relative contributions of thickness scores. In the later stages of 4. Forearms and Upper Arms: Exami- fibrosis versus edema (high frequency S S c, skin can at ro p hy and become nation may include the volar sur- ultrasound) (16). ab n o rm a l ly thin. Even though such faces but scoring should emphasize The reproducibility of these measures patients may have considerable under- the findings on the dorsal aspect of b e t ween individual inve s t i gat o rs and lying tethering of the skin (adherence the forearms and upper arms. d i ffe rent re s e a rch centers re m a i n s of skin to underlying subcutaneous tis- 5. Chest: Assess from the manubrial untested, but their increased objectivity sue, making it difficult to “pick up”), notch to the xiphoid, including the and the potential for enhanced sensitiv-

S-6 Skin, joint, tendon and muscle involvement in SSc / A. Akesson et al. ity to change is attractive. All risk the sors and flexors of both the fingers and Table I. Core set variables for the assess- problem of sampling error, not unlike the wrists; the olecranon bu rsae; the ment of skin, j o i n t , tendon and mu s cl e the use of skin biopsy. Local skin scores shoulder capsule; the knee extensors; involvement. by MRSS have been validated in terms and the ex t e n s o rs and fl ex o rs of the of their correlation with core skin biop- ankles, including the Achille tendons. Skin modified Rodnan Skin Score sy weights but not in terms of local dif- Joints DAS 28 (when occurs) fe rences in histopat h o l ogy, fi b ro bl a s t Muscle involvement Tendons Tendon friction rubs behaviour or gene expression (17, 18). Proximal muscle weakness, principally Muscle CPK, proximal weakness of the shoulder and hip girdles, is a Joint involvement common clinical feature of SSc, most Proliferative synovitis and other forms notably in patients with diffuse sclero- of primary joint involvement have been d e rma. Insidious onset of we a k n e s s , Discussion described in scleroderma but may be flexor greater than extensor, but in the Identification of core set variables ove re s t i m at e d. Local skin thicke n i n g absence of significant muscle pain and After a critical review of the available and invo l vement of the tendons and tenderness is the most typical scenario l i t e rat u re and group discussion, t h e tendons sheaths are frequently a better, (24). subcommittee propose as core set vari- albeit underap p re c i at e d, ex p l a n at i o n Detailed studies have revealed that a ables for the assessment of skin, joint, for loss of joint mobility, local pain and simple is the tendon and muscle involvement those impaired function. most prevalent lesion, although overlap listed in Table I. In multicenter interventional trials, the with poly myo s i t i s , piecemeal infa rc- p resence of synovitis has been mea- tion from scl e ro d e rma va s c u l o p at hy, Rationale for selecting the core set s u red as a “ m o d i fied Ritchie index ” fi b rous myo p at hy (24-26) and myo - variables where the presence of swelling and ten- p athies of uncertain pat h ogenic re l a- The mRSS has evolved to serve as the d e rness of the metacarp o p h a l a n ge a l tionship are also well described.Weak- primary outcome measure in virtually joints, wrists, elbows and knees have ness can be attributed to the adverse all clinical interventional trials by the been re c o rd e d. This simplified ap- effects of therapy, e.g. , community of international scleroder- proach remains unvalidated and proba- but may also be related to articular/ten- ma researchers. The mRSS has been bly insufficiently precise (19). dinous involvement, disuse and seden- thoroughly studied (6-8) and has been Our subcommittee recommended the tary activity levels. found to be accurate (inter- o b s e rve r DAS-28 (20) as a core assessment tech- Assessment of muscle strength by con- variability of 5 units) and reproducible nique in all clinical descriptive investi- frontational testing is difficult to inter- ( i n t ra - o b s e rver va ri ability of 3 units) gation in patients with scl e ro d e rm a . pret in the setting of local tendon in- (8). This standard of utility exceeds that This instrument has evolved to serve as fl a m m ation and reduced mobility. of techniques utilized in studies of a core clinical measurement for rheu- S e rum mu s cle enzyme assay s , m o s t rheumatoid arthritis (joint count). The matoid arthritis and is widely used and notably creatine phosphokinase (CPK), MRSS is accessible and cost effective, understood by the general community are both sensitive and specific. Eleva- in that it is a simple bedside examina- of rheumatologists (21). tions above 3 to 4 times the upper limit tion requiring less than 5 minutes to of normal are indicative of polymyosi- perform. Tendon involvement tis (24, 27). The DAS-28 is accessibl e, va l i d at e d A tendon friction rub is defined as A core assessment for the presence or and sensitive to change in non-sclero- “leathery crepitus” noted on palpation absence of muscle disease must consid- derma populations. Prospective multi- during active or passive motion of a er the multiple methodologies that offer center data gathering on scleroderma joint. Their presence has been ascribed high precision, e.g. magnetic resonance patients can test the usefulness of this to fi b rous or fi b rinous tendinitis or i m aging or electro myograp hy, bu t measure. (22, 23). should also recognize that these tech- Tendon rubs are highly specific fo r The presence of one or more tendon niques are neither broadly nor uniform- s cl e ro d e rma with diffuse cutaneous friction rubs is thus a crucial core vari- ly accessible and that they are expen- involvement which is early and active. able in clinical descriptive investigation sive. Their presence corre l ates with more in scle ro d e r ma. These rubs confer stron g The re c o m m e n d ation for descri p t ive severe skin thickening, more frequent pre d i c t i ve value regar ding cla s s i fi c at i o n , core assessments applicable to all pa- h e a rt and kidney invo l vement and severity and progression and should be tients with systemic sclerosis is to per- decreased survival. incorporated into both clinical practice form the following: 1) physical exami- The detection of proximal we a k n e s s and descri p t ive clinical inve s t i gat i o n . nation of proximal muscles for weak- and the evaluation of serum CPK can All patients should be assessed by pal- ness (neck flexion, shoulder girdle, hip identify SSc patients with muscle dis- p ation during active and/or passive girdle); 2) serum CPK level; and 3) if ease, even if its nature may require fur- motion in the following areas: exten- in d i c at e d , EM G , MRI or mus c le biopsy. ther investigations.

S-7 Skin, joint, tendon and muscle involvement in SSc / A. Akesson et al.

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