- Email: [email protected]
(i) Medical management of the rheumatoid hand
Current Orthopaedics (2001) 15, 323^328
c 2002 Elsevier Science Ltd. All rights reserved. doi:10.1054/cuor.2001.0214, available online at http://www.idealibrary.com on
MINI-SYMPOSIUM: RHEUMATOID DISEASE OF THE HAND AND WRIST
(i) Medical management of the rheumatoid hand Douglas J. Veale Department of Rheumatology, St.Vincent’s University Hospital, Elm Park, Dublin 4, Ireland
KEYWORDS rheumatoid hand, early diagnosis, ultrasound, anti-TNF
Summary In this review, we consider the assessment and treatment of the rheumatoid hand.The combination of rapid technological advance in diagnostics and biological therapies, such as anti-TNF has transformed this area of rheumatological practice in recent years.The emphasis of rheumatoid arthritis (RA) management has changed in the past10 years to early diagnosis and treatment, with Early Arthritis Clinics being widely established.This has stimulated a search for improved methods of diagnosis before the development of damage and characteristic deformity.The basis for this paradigm shift is thatdrug therapy can preventdamage/deformity and maintain function.Simultaneously, the therapeutic approach has shifted with aggressive therapy being introduced earlier. High-resolution ultrasound (HRUS), and needle arthroscopy used as predominantly research tools may have practical applications in the clinic. In conclusion, signi¢cant improvement in the assessment and treatment of the rheumatoid hand at an early stage c 2002 Elsevier Science Ltd. All rights reserved. may prevent deformity.
INTRODUCTION Rheumatoid arthritis (RA) is a chronic, progressive in£ammatory disease of the joints but may a¡ect other organ systems. Initially, RA most commonly a¡ects the small joints of the hand and wrist in a symmetrical fashion, and it has a predilection for the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints in the ¢rst instance. The distal interphalangeal (DIP) joints are spared in the vast majority of cases. It may occasionally present, however, as a monoarthritis of a large joint, such as the knee or shoulder. It is an autoimmune disease, which is de¢ned clinically by the pattern of joint involvement and synovial swelling which is often described as ‘boggy’ due to the in£ammatory nature of the synovial pathology. It may also be associated with the presence of circulating rheumatoid factor in the serum in 85% of patients, this is most commonly an IgM antibody directed against an IgG molecule. The test for rheumatoid factor is of some diagnostic use. However as it is not always present, especially in early disease, RA should not be excluded on the basis of a negative test. The rheumatoid hand is therefore critical in the assessment of patients suspected of early or recent onset *Correspondence to: DJV. Tel.: 00353-1-2094781; Fax: 00353-1-2839420; E-mail: [email protected].
RA. If we are to prevent joint damage, limit deformity and thereby preserve function it is imperative to identify the ‘rheumatoid hand’ before it develops the welldescribed characteristic anatomical changes of longstanding disease. These changes include boutonniere or swan-neck deformities, ulnar deviation of the ¢ngers and subluxation of the MCP and wrist joints. This is the basis for the development of Early Arthritis Clinics that have been established throughout the UK, Europe and the US.1 These clinics are dedicated to detecting synovitis early and initiating more aggressive therapy at an appropriate stage. In recent years, algorithms have been developed to identify individuals at high risk of RA, based on clinical features such as gender, family history and laboratory investigations such as Creactive protein, rheumatoid factor and even genetic typing using the shared epitope. It has been demonstrated that the third hypervariable region of the HLA DR4 molecule is associated with RA, although it remains unclear whether it is a marker for susceptibility or severity. Recent studies show that clinical examination of the rheumatoid hand is relatively poor at detecting lowgrade or early synovitis and therefore more sensitive diagnostic methods are needed.2 Diagnostic approaches in early disease have been under intense focus in the last10 years as rapid technological development of imaging techniques such as highresolution ultrasound (HRUS) and magnetic resonance
324
imaging (MRI) o¡er speci¢c advantages over conventional techniques. Therapeutic strategies have also changed rapidly over the past 20 years, and most recently have been transformed with the introduction of combination therapeutic approaches and the development of biologic agents. This paper will address the principles of management applied speci¢cally to the rheumatoid hand, in the context of these changes in diagnostic techniques and the potential for therapy.
DIAGNOSTIC INVESTIGATIONS The plain radiograph is very insensitive often only demonstrating abnormalities such as bone erosion at a late
CURRENT ORTHOPAEDICS
stage of disease. Technological development and improved capabilities of HRUS and MRI have been highlighted by a number of studies.3 The plain X-ray cannot detect changes in soft tissue such as synovitis or early erosive damage at the articular margins, which are the hallmark of the rheumatoid hand, while HRUS is highly sensitive at detecting these changes4 ^ 8 (Fig. 1). Furthermore, while MRI is more sensitive than plain radiography, it may have lower speci¢city than HRUS. MRI is more invasive, requiring gadolinium injection for maximum information regarding activity of synovitis. The additional bene¢ts of HRUS include maximum application to the entire joint margins especially in the ¢rst and second MCP joints, which are most likely involved ¢rst in the rheumatoid hand. HRUS, however, provides poor access
Figure 1 (A) The clinical appearance ofthe early rheumatoid hand with marked softtissue swelling of the second metacarpophalangealjoint, (B) the plainradiograph shows a suspicion of an erosion but no de¢nite corticalbreak, and (C) the high-resolution ultrasound shows a de¢nite erosion with cortical disruption (arrow).
MEDICAL MANAGEMENT OF THE RHEUMATOID HAND
to certain joint surfaces such as the retropatellar and deep interdigital web spaces as these areas may be blind spots. HRUS is relatively low cost in comparison to MRI, although it is very much operator-dependant and qualitative, while dynamic MRI data can be more easily quanti¢ed using computer assisted analysis.
325 Table 1 The current uses for Ultrasoundin musculoskeletal disease 1. An extension to clinical examination 2. Detection and quanti¢cation of synovitis 3. Assessment of ligament, tendon and muscle integrity 4. Isolation and aspiration of joint £uid 5. Detection of loose bodies 6. Guiding procedures e.g. injection/biopsy
HRUS and the rheumatoid hand Examination In a recent study patients have undergone standard clinical assessment and a diagnosis and management plan have been proposed. Following this an HRUS of the clinically a¡ected area has been undertaken in the outpatients and its e¡ect on diagnosis and management recorded. So far 52 patients have been studied. In 28 (54%) the diagnosis has been altered by the HRUS examination (2=disease, 26=anatomical site), while the proposed management has been altered following HRUS in 29 (56%). This preliminary work suggests that HRUS has an impact on diagnosis and management in the majority of patients who have undergone scanning. Larger numbers of patients will need to be studied and recruitment is ongoing, with more speci¢c outcome measures being employed. Recent studies of detection of synovitis have demonstrated increased sensitivity over clinical examination, with synovitis being detected in over 10 times more frequently in MTP joints using HRUS.2
Table 2. Practice points High-resolution ultrasound in musculoskeletal disease: K
K K
o¡ers good imaging of super¢cial musculoskeletal structures is non-invasive and inexpensive is widely available and has no adverse e¡ects
Table 3. Research directions High-resolution ultrasound in musculoskeletal disease: K
K K
May improve diagnosis of early synovitis of the MCP/ PIP joints of the RA hand May provide improved therapeutic intervention May provide a more sensitive outcome measure for response to therapy
has been shown to translate into an improved clinical outcome (Tables1^3).
HRUS guided intervention
Needle arthroscopy
The use of HRUS in the guidance of therapeutic and diagnostic procedures has not surprisingly generated a great deal of interest. Arthrocentesis or other diagnostic aspiration procedures may be accurately guided by HRUS.9 Fluoroscopic techniques have traditionally been used in this role but o¡er less visualization of needle location, increased exposure to ionizing radiation and poorer soft tissue assessment. HRUS has also been used as a research tool in studies of the early rheumatoid hand to guide the biopsy of erosions at the MCP joints.10 Therapeutic procedures may also be enhanced by the use of HRUS. It has been demonstrated that injections guided by clinical parameters are inaccurate, irrespective of the experience of the practitioner. HRUS has been very useful for local therapeutic intervention in tenosynovitis of the £exor and the extensor tendon sheaths of the rheumatoid hand, and also if there is dactyilitis present which appears to result from in£ammation of the intra-articular and the peri-tendinous synovial tissue.11 Accuracy of needle placement and therefore steroid injection may be improved by the use of HRUS and this
The ¢rst arthroscopy was not performed until 1918 when Professor Takagi of Tokyo examined a knee joint using a cystoscope 7.3 mm in diameter; however, an important development came in1959 with the introduction of the Watanabe 21 arthroscope. Technological advances have been remarkably rapid with ¢bre-optic telescopes of 1mm diameter and rod lens telescopes of 2.4 mm allowing examination of small joints including MCPs, safely under local anaesthesia.12 Arthroscopy is established for assessing synovitis and chondropathy, to perform synovial membrane (SM) biopsy, joint lavage and to administer therapy. It is an invasive procedure with potential adverse e¡ects; however in one study, 88% reported arthroscopy to be tolerable. A review of a large number of studies has also reported arthroscopy to be acceptable to patients.
Research role of needle arthroscopy Recent technological developments of 1^2 mm telescopes, linked with improved therapeutic potential provides the rationale for the study of early arthritis.
326
However this research tool is still at an early stage of develpoment.12,13 Diagnostic technologies including needle arthroscopy, high-frequency ultrasonography and MRI have developed rapidly, and their role in clinical practice remains unproven at this time. Comparison of di¡erent imaging modalities will provide useful information that may allow ‘calibration’ of techniques and a greater understanding of the pathogenesis of RA.4,13,14. There was strong correlation between MRI and arthroscopic assessment both for the global and regionof-interest scores, which has given a unique insight into the use of these techniques. One of these studies provided the basis for further applications of MRI with gadolinium enhancement for the assessment of synovitis in the MCP joints of early rheumatoid hands.15 The detection of highly in£amed synovial tissue within an active erosion on MRI provides an entirely new dimension of imaging, when the same hand imaged with conventional plain radiography may appear completely normal. The combination of MRI and needle arthroscopy assessment has been successfully applied to several clinical research trials, and this represents the most sensitive and modern technology being used in the assessment of new therapeutic agents for the treatment of early RA.16
Synovial examination The examination of the synovial tissue by direct visualization is only one aspect of our understanding of the numerous types of arthritis, the microscopic examination is very much more complex. It may provide even greater understanding in the future as new laboratory technologies allow analysis on a genetic as well as a molecular and cellular level.17,18
Assessment of response to therapy The sequential imaging study14 demonstrated the ability of arthroscopy and MRI imaging to reliably detect changes within the joint, in response to therapy. A number of clinical studies of drug therapy using this approach are currently underway which should allow further validation of this approach. Finally, novel gene therapy techniques can also be monitored in this way.
THERAPEUTIC INTERVENTION Drug therapy for RA had changed little until 15 years ago; the ¢rst-line treatment was non-steroidal anti-in£ammatory drugs and second-line drugs included gold salts, Sulphasalazine, Penicillamine and corticosteroids. Sulphasalazine and Methotrexate are still the most widely used disease-modifying anti-rheumatic drugs (DMARDs) as they are e¡ective alone and in combination, have a low incidence of adverse e¡ects and there-
CURRENT ORTHOPAEDICS fore patient tolerability is good.19 The adoption of a new paradigm to treat RA early, before the development of the classical deformities of the hand, required greater efforts in drug development.1 The focus of this e¡ort has centred on proin£ammatory cytokines in particularFtumor necrosis factor alpha (TNFa) and interleukin-1 (IL-1). Recently, there has been a rapid acceleration in the development of new drugs including anti-metabolites such as le£unomide and biologic agents designed to block cytokines, which includes drugs such as TNFa blockers and the IL-1receptor antagonist (IL1ra).Overall, the treatment paradigm shift has been a move to more aggressive therapy with DMARD combinations at an early stage of disease and a recent study suggests that this approach may have shown some promising results.19
Novel biologic therapies for treatment of the rheumatoid hand The main development in the treatment of early RA in the past ¢ve years has been the advent of TNFa and IL-1 receptor blockers, both these cytokines appearing to be the key in driving the in£ammatory process in RA. Drugs have therefore been designed as monoclonal antibodies or fusion proteins which bind and neutralize the molecule or cytokine receptor blockers, which occupy the receptor site and thus inhibit their pro-in£ammatory actions. This topic has been clearly summarized by Choy and Panayi, in a review in the New England Journal of Medicine, which is recommended for further reading.20
Prediction of prognosis and response to therapy This raises the issue of introducing therapy at an early stage before extensive joint damage/deformity and systemic disease activity reduce the potential for the patient to respond or irrevocably alter the baseline health status of the patient. It is therefore imperative that we can identify which patients have (1) a poor prognosis and (2) the potential to respond to speci¢c therapies. We are currently still unable to accurately predict at an early stage of disease, before the hand joints have been damaged, which patients are destined to progress. Although a number of factors are strong predictors of outcome, such as female gender, Rheumatoid factor and the presence of nodules, these may not be present early in the disease. It is imperative therefore that we continue to search for markers which will improve the prediction of prognosis.This will only come if investigations, such as needle arthroscopy, HRUS and MRI are undertaken as part of clinical research protocols. The technological capability to identify patients who will respond to speci¢c therapeutic interventions is now within our grasp.The rapid developments of tech-
MEDICAL MANAGEMENT OF THE RHEUMATOID HAND
nology, in particular molecular biology using proteinomics and genomics, may indeed allow the identi¢cation of speci¢c patient characteristics, which will predict which patients will respond to which therapy. This is, undoubtedly, the future of pharmaceutical development for the modi¢cation of chronic diseases such as RA, until a cure can be found.
SPECIFIC PROBLEMS RELATING TO THE RHEUMATOID HAND Tenosynovitis In£ammation of the synovial sheath covering tendons is a common clinical problem and often may be the presenting feature of the rheumatoid hand. It is most apparent when it occurs in the extensor tendon sheath over the dorsum of wrist and hand. It is evident as a ‘boggy’, £uctuant swelling. This is usually clinically obvious and easily injected with corticosteroid; however with the advent of HRUS it is possible to con¢rm the injection site and delivery of steroid solution if desirable.Tenosynovitis of the £exor tendon sheaths is less obvious clinically. The patient may complain of swelling on the palmar aspect of the hand, over the MCP joint. Alternatively, it may present as ‘triggering’ or ‘locking’ of the £exed ¢nger, which then must be passively extended by the patient. On examination, crepitus is usually felt on the palmar aspect of the MCP joint while the ¢nger is actively £exed and extended. HRUS is particularly useful for identifying the £exor tendon sheath, and avoiding the tendon, for steroid injection. Tendon rupture may occur especially if in£ammatory change is severe, or if the tendon passes over a bony prominence.
Carpal tunnel syndrome This is a secondary e¡ect of swelling at the wrist joint and therefore RA may present with symptoms of the carpal tunnel syndrome. The median nerve readily becomes compressed as it passes deep to the £exor retinaculum. The patient classically complains of pins and needles, numbness or tingling in the thumb, index, middle and half of the ring ¢nger. Symptoms often wake the patient at night.Treatment is aimed at controlling the underlying disease activity; however steroid injection into the carpal tunnel may be e¡ective, occasionally surgical release being required.
327
tendon sheaths; however they may occur over the MCP and PIP joints of the rheumatoid hand. Nodules are usually ¢rm and may be tender; they are associated with disease severity; however they may come and go relatively quickly. Interestingly, rheumatoid nodulosis may be accelerated by the DMARDFMethotrexate.The mechanism of this e¡ect is not clear, but the drug may need to be stopped if the nodules become very numerous. Intranodular steroid injections have been used with some success. Surgical removal is not usually recommended.
Vasculitis RA may be associated with a systemic cutaneous vasculitis. Histologically this is a leucocytoclastic peri-vascular lesion. It often presents with small nail-fold infarcts or splinter haemorrhages which manifest at the nail-fold or nail-bed of the ¢nger tips. In some cases the ischaemic changes may be more profound with digital ulceration or infarction resulting. It is not uncommon for nodules and cutaneous vasculitis to coexist, with the nodule tips becoming ischaemic.
SUMMARY It is clear that signi¢cant and rapid advances in the assessment and management of RA are currently underway, facilitated by the development of new technologies such as HRUS, MRI and needle arthroscopy along with novel therapeutic options such as anti-TNFa and IL1ra. The paradigm shift towards early diagnosis and aggressive therapy highlights the importance of the ‘rheumatoid hand’, as the majority of patients present ¢rst with symptoms of involvement of the MCP/PIP and/or wrist joints.Furthermore, this paradigm is based on the detection of disease before joint damage and deformity have become established, to prevent such changes and maintain hand function. Speci¢c problems and solutions of the rheumatoid hand such as tenosynovitis, trigger ¢nger, carpal tunnel syndrome and nodules are discussed; however, overall control of the disease systemically is the best therapeutic strategy. Finally, ultimate re¢nement of the assessment process should aim to identify those patients who have a poor prognosis and to which therapies individual patients will respond; this is a realistic goal as the molecular technologies now exist.
RESEARCH DIRECTIONS K
Nodules The rheumatoid nodule has been well described clinically and histopathologically. It occurs in up to 50% of RA patients. Nodules are subcutaneous and commonly occur over pressure points such as the elbows, in bursae or
K
K K
Validation of di¡erent imaging modalities Characterization of pathogenic mechanisms in synovial tissue Molecular and genetic analysis of synovial tissue Monitoring of new therapy e.g. biologic agents/gene technology
328
PRACTICE POINTS Novel therapeutic approaches to the rheumatoid hand: K Early diagnosis and overall disease control are the best treatment for the rheumatoid hand K New biologic agents such as anti-TNF and IL1 Receptor Antagonists are proving highly e¡ective K Prediction of responders using molecular biology is the future aim
REFERENCES 1. Emery P. The optimal management of early rheumatoid disease: the key to preventing disability. Br J Rheumatol 1994; 33: 765^768. 2. Wake¢eld R J, Karim Z, Conaghan P G et al. Sonography is more sensitive at detecting synovitis in the metatarsophalangeal joints than clinical examination. Arthritis Rheum1999; 42: S352. 3. Fraser A,Veale D J.What practical skills do rheumatologists of the future need? Baillieres Best Pract Res Clin Rheumatol 2000; 14(4): 635^ 648. 4. Wake¢eld R J, Gibbon W W, Conaghan P et al. The value of sonography in the detection of cortical bone erosions: A comparative study with conventional radiography. Arthritis Rheum 2000; 43: 2762^2770. 5. Gibbon W W, Wake¢eld R J. Ultrasound in in£ammatory disease. Radiol Clin North Am 1999; 37(4): 633^ 651. 6. Manger B, Kalden J. Joint and connective tissue ultrasonographyF A rheumatological bedside procedure? Arthritis Rheum 1995; 38: 736 ^742. 7. Gibbon W W. Musculoskeletal ultrasound. Baillieres Clin Rheumatol 1996; 10(4): 561^588. 8. Adler R S. Future and new developments in musculoskeletal ultrasound. Radiol Clin North Am 1999; 37(4): 623^ 633. 9. Farin P U, Rasanen H, Jaroma H, Harju A. Rotator cu¡ calci¢cations: treatment with ultrasound-guided percutaneous needle aspiration and lavage. Skeletal Radiol 1996; 25: 551^554.
CURRENT ORTHOPAEDICS
10. McGonagle D,Gibbon W, Blythe D, Wake¢eld R,Green M,Veale D J, Emery P. A preliminary study of ultrasound aspiration of bone erosion in early rheumatoid arthritis. Br J Rheumatol 1999; 38: 329^331. 11. Wake¢eld R J, Emery P, Veale D J. Ultrasonography and psoriatic arthritis. J Rheumatol 2000; 27(6): 1564 ^1565. 12. Veale D J. The role of arthroscopy in early arthritis. Clin Exp Rheumatol 1999; 17: 37^38. 13. Ostendorf B, Dann P, Kocot D, Modder U, Schulitz K-P, Schneider M. Micro-arthroscopy versus MRI of MCP-joints in rheumatoid arthritis: comparing assessment of joint pathology detection. Arthritis Rheum 1997; 40 (Suppl 9): S151. 14. Veale D J, Reece R J, Orgles C S et al. Intra-articular therapy with anti-CD4 monoclonal antibody in RA: a magnetic resonance and arthroscopic study. Ann Rheum Dis 1999; 58: 342^349. 15. Ostergaard M, Klarlund M, Lassere M et al. Interreader agreement in the assessment of magnetic resonance images of rheumatoid arthritis wrist and ¢nger jointsFan international multicenter study. J Rheumatol 2001; 28:1143^1150. 16. Kraan M C, Reece R, Barg E C et al. Expression of ICAM-1 and MMP-1 in Rheumatoid synovial tissue after treatment with le£unomide or methotrexate. Arthritis Rheum 2000; 43: 1820 ^1830. 17. Ali M, Ponchel F, Wilson K E, et al. Rheumatoid arthritis synovial T cells regulate transcription of several genes associated with antigen-induced anergy. J Clin Invest 2001; 107(4): 519^528. 18. Kempsell K E, Cox C J, McColm A A et al. Detection of mycobacterium tuberculosis group organisms in human and mouse joint tissue by reverse transcriptase PCR: prevalence in diseased synovial tissue suggests lack of speci¢c association with rheumatoid arthritis. Infect Immun 2001; 69(3): 1821^1831. 19. Proudman S M, Conaghan P, Richardson C et al.Treatment of poor prognosis early rheumatoid arthritis: A randomised study of methotrexate, cyclosporin A and intra-articular corticosteroids compared with sulphasalazine alone. Arthritis Rheum 2000; 43: 1809^1819. 20. Choy E H S, Panayi G S. Mechanisms of disease: cytokine pathways and joint in£ammation in rheumatoid arthritis. N Eng J Med 2001; 344: 907^916.
c 2002 Elsevier Science Ltd. All rights reserved. doi:10.1054/cuor.2001.0214, available online at http://www.idealibrary.com on
MINI-SYMPOSIUM: RHEUMATOID DISEASE OF THE HAND AND WRIST
(i) Medical management of the rheumatoid hand Douglas J. Veale Department of Rheumatology, St.Vincent’s University Hospital, Elm Park, Dublin 4, Ireland
KEYWORDS rheumatoid hand, early diagnosis, ultrasound, anti-TNF
Summary In this review, we consider the assessment and treatment of the rheumatoid hand.The combination of rapid technological advance in diagnostics and biological therapies, such as anti-TNF has transformed this area of rheumatological practice in recent years.The emphasis of rheumatoid arthritis (RA) management has changed in the past10 years to early diagnosis and treatment, with Early Arthritis Clinics being widely established.This has stimulated a search for improved methods of diagnosis before the development of damage and characteristic deformity.The basis for this paradigm shift is thatdrug therapy can preventdamage/deformity and maintain function.Simultaneously, the therapeutic approach has shifted with aggressive therapy being introduced earlier. High-resolution ultrasound (HRUS), and needle arthroscopy used as predominantly research tools may have practical applications in the clinic. In conclusion, signi¢cant improvement in the assessment and treatment of the rheumatoid hand at an early stage c 2002 Elsevier Science Ltd. All rights reserved. may prevent deformity.
INTRODUCTION Rheumatoid arthritis (RA) is a chronic, progressive in£ammatory disease of the joints but may a¡ect other organ systems. Initially, RA most commonly a¡ects the small joints of the hand and wrist in a symmetrical fashion, and it has a predilection for the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints in the ¢rst instance. The distal interphalangeal (DIP) joints are spared in the vast majority of cases. It may occasionally present, however, as a monoarthritis of a large joint, such as the knee or shoulder. It is an autoimmune disease, which is de¢ned clinically by the pattern of joint involvement and synovial swelling which is often described as ‘boggy’ due to the in£ammatory nature of the synovial pathology. It may also be associated with the presence of circulating rheumatoid factor in the serum in 85% of patients, this is most commonly an IgM antibody directed against an IgG molecule. The test for rheumatoid factor is of some diagnostic use. However as it is not always present, especially in early disease, RA should not be excluded on the basis of a negative test. The rheumatoid hand is therefore critical in the assessment of patients suspected of early or recent onset *Correspondence to: DJV. Tel.: 00353-1-2094781; Fax: 00353-1-2839420; E-mail: [email protected].
RA. If we are to prevent joint damage, limit deformity and thereby preserve function it is imperative to identify the ‘rheumatoid hand’ before it develops the welldescribed characteristic anatomical changes of longstanding disease. These changes include boutonniere or swan-neck deformities, ulnar deviation of the ¢ngers and subluxation of the MCP and wrist joints. This is the basis for the development of Early Arthritis Clinics that have been established throughout the UK, Europe and the US.1 These clinics are dedicated to detecting synovitis early and initiating more aggressive therapy at an appropriate stage. In recent years, algorithms have been developed to identify individuals at high risk of RA, based on clinical features such as gender, family history and laboratory investigations such as Creactive protein, rheumatoid factor and even genetic typing using the shared epitope. It has been demonstrated that the third hypervariable region of the HLA DR4 molecule is associated with RA, although it remains unclear whether it is a marker for susceptibility or severity. Recent studies show that clinical examination of the rheumatoid hand is relatively poor at detecting lowgrade or early synovitis and therefore more sensitive diagnostic methods are needed.2 Diagnostic approaches in early disease have been under intense focus in the last10 years as rapid technological development of imaging techniques such as highresolution ultrasound (HRUS) and magnetic resonance
324
imaging (MRI) o¡er speci¢c advantages over conventional techniques. Therapeutic strategies have also changed rapidly over the past 20 years, and most recently have been transformed with the introduction of combination therapeutic approaches and the development of biologic agents. This paper will address the principles of management applied speci¢cally to the rheumatoid hand, in the context of these changes in diagnostic techniques and the potential for therapy.
DIAGNOSTIC INVESTIGATIONS The plain radiograph is very insensitive often only demonstrating abnormalities such as bone erosion at a late
CURRENT ORTHOPAEDICS
stage of disease. Technological development and improved capabilities of HRUS and MRI have been highlighted by a number of studies.3 The plain X-ray cannot detect changes in soft tissue such as synovitis or early erosive damage at the articular margins, which are the hallmark of the rheumatoid hand, while HRUS is highly sensitive at detecting these changes4 ^ 8 (Fig. 1). Furthermore, while MRI is more sensitive than plain radiography, it may have lower speci¢city than HRUS. MRI is more invasive, requiring gadolinium injection for maximum information regarding activity of synovitis. The additional bene¢ts of HRUS include maximum application to the entire joint margins especially in the ¢rst and second MCP joints, which are most likely involved ¢rst in the rheumatoid hand. HRUS, however, provides poor access
Figure 1 (A) The clinical appearance ofthe early rheumatoid hand with marked softtissue swelling of the second metacarpophalangealjoint, (B) the plainradiograph shows a suspicion of an erosion but no de¢nite corticalbreak, and (C) the high-resolution ultrasound shows a de¢nite erosion with cortical disruption (arrow).
MEDICAL MANAGEMENT OF THE RHEUMATOID HAND
to certain joint surfaces such as the retropatellar and deep interdigital web spaces as these areas may be blind spots. HRUS is relatively low cost in comparison to MRI, although it is very much operator-dependant and qualitative, while dynamic MRI data can be more easily quanti¢ed using computer assisted analysis.
325 Table 1 The current uses for Ultrasoundin musculoskeletal disease 1. An extension to clinical examination 2. Detection and quanti¢cation of synovitis 3. Assessment of ligament, tendon and muscle integrity 4. Isolation and aspiration of joint £uid 5. Detection of loose bodies 6. Guiding procedures e.g. injection/biopsy
HRUS and the rheumatoid hand Examination In a recent study patients have undergone standard clinical assessment and a diagnosis and management plan have been proposed. Following this an HRUS of the clinically a¡ected area has been undertaken in the outpatients and its e¡ect on diagnosis and management recorded. So far 52 patients have been studied. In 28 (54%) the diagnosis has been altered by the HRUS examination (2=disease, 26=anatomical site), while the proposed management has been altered following HRUS in 29 (56%). This preliminary work suggests that HRUS has an impact on diagnosis and management in the majority of patients who have undergone scanning. Larger numbers of patients will need to be studied and recruitment is ongoing, with more speci¢c outcome measures being employed. Recent studies of detection of synovitis have demonstrated increased sensitivity over clinical examination, with synovitis being detected in over 10 times more frequently in MTP joints using HRUS.2
Table 2. Practice points High-resolution ultrasound in musculoskeletal disease: K
K K
o¡ers good imaging of super¢cial musculoskeletal structures is non-invasive and inexpensive is widely available and has no adverse e¡ects
Table 3. Research directions High-resolution ultrasound in musculoskeletal disease: K
K K
May improve diagnosis of early synovitis of the MCP/ PIP joints of the RA hand May provide improved therapeutic intervention May provide a more sensitive outcome measure for response to therapy
has been shown to translate into an improved clinical outcome (Tables1^3).
HRUS guided intervention
Needle arthroscopy
The use of HRUS in the guidance of therapeutic and diagnostic procedures has not surprisingly generated a great deal of interest. Arthrocentesis or other diagnostic aspiration procedures may be accurately guided by HRUS.9 Fluoroscopic techniques have traditionally been used in this role but o¡er less visualization of needle location, increased exposure to ionizing radiation and poorer soft tissue assessment. HRUS has also been used as a research tool in studies of the early rheumatoid hand to guide the biopsy of erosions at the MCP joints.10 Therapeutic procedures may also be enhanced by the use of HRUS. It has been demonstrated that injections guided by clinical parameters are inaccurate, irrespective of the experience of the practitioner. HRUS has been very useful for local therapeutic intervention in tenosynovitis of the £exor and the extensor tendon sheaths of the rheumatoid hand, and also if there is dactyilitis present which appears to result from in£ammation of the intra-articular and the peri-tendinous synovial tissue.11 Accuracy of needle placement and therefore steroid injection may be improved by the use of HRUS and this
The ¢rst arthroscopy was not performed until 1918 when Professor Takagi of Tokyo examined a knee joint using a cystoscope 7.3 mm in diameter; however, an important development came in1959 with the introduction of the Watanabe 21 arthroscope. Technological advances have been remarkably rapid with ¢bre-optic telescopes of 1mm diameter and rod lens telescopes of 2.4 mm allowing examination of small joints including MCPs, safely under local anaesthesia.12 Arthroscopy is established for assessing synovitis and chondropathy, to perform synovial membrane (SM) biopsy, joint lavage and to administer therapy. It is an invasive procedure with potential adverse e¡ects; however in one study, 88% reported arthroscopy to be tolerable. A review of a large number of studies has also reported arthroscopy to be acceptable to patients.
Research role of needle arthroscopy Recent technological developments of 1^2 mm telescopes, linked with improved therapeutic potential provides the rationale for the study of early arthritis.
326
However this research tool is still at an early stage of develpoment.12,13 Diagnostic technologies including needle arthroscopy, high-frequency ultrasonography and MRI have developed rapidly, and their role in clinical practice remains unproven at this time. Comparison of di¡erent imaging modalities will provide useful information that may allow ‘calibration’ of techniques and a greater understanding of the pathogenesis of RA.4,13,14. There was strong correlation between MRI and arthroscopic assessment both for the global and regionof-interest scores, which has given a unique insight into the use of these techniques. One of these studies provided the basis for further applications of MRI with gadolinium enhancement for the assessment of synovitis in the MCP joints of early rheumatoid hands.15 The detection of highly in£amed synovial tissue within an active erosion on MRI provides an entirely new dimension of imaging, when the same hand imaged with conventional plain radiography may appear completely normal. The combination of MRI and needle arthroscopy assessment has been successfully applied to several clinical research trials, and this represents the most sensitive and modern technology being used in the assessment of new therapeutic agents for the treatment of early RA.16
Synovial examination The examination of the synovial tissue by direct visualization is only one aspect of our understanding of the numerous types of arthritis, the microscopic examination is very much more complex. It may provide even greater understanding in the future as new laboratory technologies allow analysis on a genetic as well as a molecular and cellular level.17,18
Assessment of response to therapy The sequential imaging study14 demonstrated the ability of arthroscopy and MRI imaging to reliably detect changes within the joint, in response to therapy. A number of clinical studies of drug therapy using this approach are currently underway which should allow further validation of this approach. Finally, novel gene therapy techniques can also be monitored in this way.
THERAPEUTIC INTERVENTION Drug therapy for RA had changed little until 15 years ago; the ¢rst-line treatment was non-steroidal anti-in£ammatory drugs and second-line drugs included gold salts, Sulphasalazine, Penicillamine and corticosteroids. Sulphasalazine and Methotrexate are still the most widely used disease-modifying anti-rheumatic drugs (DMARDs) as they are e¡ective alone and in combination, have a low incidence of adverse e¡ects and there-
CURRENT ORTHOPAEDICS fore patient tolerability is good.19 The adoption of a new paradigm to treat RA early, before the development of the classical deformities of the hand, required greater efforts in drug development.1 The focus of this e¡ort has centred on proin£ammatory cytokines in particularFtumor necrosis factor alpha (TNFa) and interleukin-1 (IL-1). Recently, there has been a rapid acceleration in the development of new drugs including anti-metabolites such as le£unomide and biologic agents designed to block cytokines, which includes drugs such as TNFa blockers and the IL-1receptor antagonist (IL1ra).Overall, the treatment paradigm shift has been a move to more aggressive therapy with DMARD combinations at an early stage of disease and a recent study suggests that this approach may have shown some promising results.19
Novel biologic therapies for treatment of the rheumatoid hand The main development in the treatment of early RA in the past ¢ve years has been the advent of TNFa and IL-1 receptor blockers, both these cytokines appearing to be the key in driving the in£ammatory process in RA. Drugs have therefore been designed as monoclonal antibodies or fusion proteins which bind and neutralize the molecule or cytokine receptor blockers, which occupy the receptor site and thus inhibit their pro-in£ammatory actions. This topic has been clearly summarized by Choy and Panayi, in a review in the New England Journal of Medicine, which is recommended for further reading.20
Prediction of prognosis and response to therapy This raises the issue of introducing therapy at an early stage before extensive joint damage/deformity and systemic disease activity reduce the potential for the patient to respond or irrevocably alter the baseline health status of the patient. It is therefore imperative that we can identify which patients have (1) a poor prognosis and (2) the potential to respond to speci¢c therapies. We are currently still unable to accurately predict at an early stage of disease, before the hand joints have been damaged, which patients are destined to progress. Although a number of factors are strong predictors of outcome, such as female gender, Rheumatoid factor and the presence of nodules, these may not be present early in the disease. It is imperative therefore that we continue to search for markers which will improve the prediction of prognosis.This will only come if investigations, such as needle arthroscopy, HRUS and MRI are undertaken as part of clinical research protocols. The technological capability to identify patients who will respond to speci¢c therapeutic interventions is now within our grasp.The rapid developments of tech-
MEDICAL MANAGEMENT OF THE RHEUMATOID HAND
nology, in particular molecular biology using proteinomics and genomics, may indeed allow the identi¢cation of speci¢c patient characteristics, which will predict which patients will respond to which therapy. This is, undoubtedly, the future of pharmaceutical development for the modi¢cation of chronic diseases such as RA, until a cure can be found.
SPECIFIC PROBLEMS RELATING TO THE RHEUMATOID HAND Tenosynovitis In£ammation of the synovial sheath covering tendons is a common clinical problem and often may be the presenting feature of the rheumatoid hand. It is most apparent when it occurs in the extensor tendon sheath over the dorsum of wrist and hand. It is evident as a ‘boggy’, £uctuant swelling. This is usually clinically obvious and easily injected with corticosteroid; however with the advent of HRUS it is possible to con¢rm the injection site and delivery of steroid solution if desirable.Tenosynovitis of the £exor tendon sheaths is less obvious clinically. The patient may complain of swelling on the palmar aspect of the hand, over the MCP joint. Alternatively, it may present as ‘triggering’ or ‘locking’ of the £exed ¢nger, which then must be passively extended by the patient. On examination, crepitus is usually felt on the palmar aspect of the MCP joint while the ¢nger is actively £exed and extended. HRUS is particularly useful for identifying the £exor tendon sheath, and avoiding the tendon, for steroid injection. Tendon rupture may occur especially if in£ammatory change is severe, or if the tendon passes over a bony prominence.
Carpal tunnel syndrome This is a secondary e¡ect of swelling at the wrist joint and therefore RA may present with symptoms of the carpal tunnel syndrome. The median nerve readily becomes compressed as it passes deep to the £exor retinaculum. The patient classically complains of pins and needles, numbness or tingling in the thumb, index, middle and half of the ring ¢nger. Symptoms often wake the patient at night.Treatment is aimed at controlling the underlying disease activity; however steroid injection into the carpal tunnel may be e¡ective, occasionally surgical release being required.
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tendon sheaths; however they may occur over the MCP and PIP joints of the rheumatoid hand. Nodules are usually ¢rm and may be tender; they are associated with disease severity; however they may come and go relatively quickly. Interestingly, rheumatoid nodulosis may be accelerated by the DMARDFMethotrexate.The mechanism of this e¡ect is not clear, but the drug may need to be stopped if the nodules become very numerous. Intranodular steroid injections have been used with some success. Surgical removal is not usually recommended.
Vasculitis RA may be associated with a systemic cutaneous vasculitis. Histologically this is a leucocytoclastic peri-vascular lesion. It often presents with small nail-fold infarcts or splinter haemorrhages which manifest at the nail-fold or nail-bed of the ¢nger tips. In some cases the ischaemic changes may be more profound with digital ulceration or infarction resulting. It is not uncommon for nodules and cutaneous vasculitis to coexist, with the nodule tips becoming ischaemic.
SUMMARY It is clear that signi¢cant and rapid advances in the assessment and management of RA are currently underway, facilitated by the development of new technologies such as HRUS, MRI and needle arthroscopy along with novel therapeutic options such as anti-TNFa and IL1ra. The paradigm shift towards early diagnosis and aggressive therapy highlights the importance of the ‘rheumatoid hand’, as the majority of patients present ¢rst with symptoms of involvement of the MCP/PIP and/or wrist joints.Furthermore, this paradigm is based on the detection of disease before joint damage and deformity have become established, to prevent such changes and maintain hand function. Speci¢c problems and solutions of the rheumatoid hand such as tenosynovitis, trigger ¢nger, carpal tunnel syndrome and nodules are discussed; however, overall control of the disease systemically is the best therapeutic strategy. Finally, ultimate re¢nement of the assessment process should aim to identify those patients who have a poor prognosis and to which therapies individual patients will respond; this is a realistic goal as the molecular technologies now exist.
RESEARCH DIRECTIONS K
Nodules The rheumatoid nodule has been well described clinically and histopathologically. It occurs in up to 50% of RA patients. Nodules are subcutaneous and commonly occur over pressure points such as the elbows, in bursae or
K
K K
Validation of di¡erent imaging modalities Characterization of pathogenic mechanisms in synovial tissue Molecular and genetic analysis of synovial tissue Monitoring of new therapy e.g. biologic agents/gene technology
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PRACTICE POINTS Novel therapeutic approaches to the rheumatoid hand: K Early diagnosis and overall disease control are the best treatment for the rheumatoid hand K New biologic agents such as anti-TNF and IL1 Receptor Antagonists are proving highly e¡ective K Prediction of responders using molecular biology is the future aim
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CURRENT ORTHOPAEDICS
10. McGonagle D,Gibbon W, Blythe D, Wake¢eld R,Green M,Veale D J, Emery P. A preliminary study of ultrasound aspiration of bone erosion in early rheumatoid arthritis. Br J Rheumatol 1999; 38: 329^331. 11. Wake¢eld R J, Emery P, Veale D J. Ultrasonography and psoriatic arthritis. J Rheumatol 2000; 27(6): 1564 ^1565. 12. Veale D J. The role of arthroscopy in early arthritis. Clin Exp Rheumatol 1999; 17: 37^38. 13. Ostendorf B, Dann P, Kocot D, Modder U, Schulitz K-P, Schneider M. Micro-arthroscopy versus MRI of MCP-joints in rheumatoid arthritis: comparing assessment of joint pathology detection. Arthritis Rheum 1997; 40 (Suppl 9): S151. 14. Veale D J, Reece R J, Orgles C S et al. Intra-articular therapy with anti-CD4 monoclonal antibody in RA: a magnetic resonance and arthroscopic study. Ann Rheum Dis 1999; 58: 342^349. 15. Ostergaard M, Klarlund M, Lassere M et al. Interreader agreement in the assessment of magnetic resonance images of rheumatoid arthritis wrist and ¢nger jointsFan international multicenter study. J Rheumatol 2001; 28:1143^1150. 16. Kraan M C, Reece R, Barg E C et al. Expression of ICAM-1 and MMP-1 in Rheumatoid synovial tissue after treatment with le£unomide or methotrexate. Arthritis Rheum 2000; 43: 1820 ^1830. 17. Ali M, Ponchel F, Wilson K E, et al. Rheumatoid arthritis synovial T cells regulate transcription of several genes associated with antigen-induced anergy. J Clin Invest 2001; 107(4): 519^528. 18. Kempsell K E, Cox C J, McColm A A et al. Detection of mycobacterium tuberculosis group organisms in human and mouse joint tissue by reverse transcriptase PCR: prevalence in diseased synovial tissue suggests lack of speci¢c association with rheumatoid arthritis. Infect Immun 2001; 69(3): 1821^1831. 19. Proudman S M, Conaghan P, Richardson C et al.Treatment of poor prognosis early rheumatoid arthritis: A randomised study of methotrexate, cyclosporin A and intra-articular corticosteroids compared with sulphasalazine alone. Arthritis Rheum 2000; 43: 1809^1819. 20. Choy E H S, Panayi G S. Mechanisms of disease: cytokine pathways and joint in£ammation in rheumatoid arthritis. N Eng J Med 2001; 344: 907^916.