Managing seronegative spondarthritides
L. Koehler,
J. G. Kuipers and
H. Zeidler
Division of Rheumatology, Department of Internal Medicine, Medical School Hannover, Carl-Neuberg Strasse 1, D 30625 Hannover, Germany
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Introduction
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Over the last several decades the classification of rheumatoid factor-negative arthritis has changed substantially. For some time it was common practice to consider psoriatic arthritis, Reiter's syndrome, and ankylosing spondylitis as atypical or special forms of rheumatoid arthritis, as reflected in the proposed classification of rheumatic diseases by the International League Against Rheumatism in 1957 [1]. As described by Moll et al. [2] the school of lumpers, who preferred to group the so-called variants of rheumatoid arthritis with rheumatoid arthritis itself, were overcome by the school of splitters, prompted by the idea that these seronegative arthritides were, in fact, entirely separate entities. This change was mirrored by the Nomenclature and Classification of the Rheumatic Diseases proposed by the American Rheumatism Association in 1963 [1]. Rheumatoid arthritis, juvenile Still's disease, ankylosing spondylitis, psoriatic arthritis, and Reiter's syndrome were then classified under separate headings with the common denominator polyarthritis of unknown origin. Finally, Moll et al. [3] developed the new concept of a closely interlinked group of seronegative arthritides, which they designated as seronegative spondarthritides. Through a series of controlled family studies and evidence from the literature, they formulated the clinical, serological, radiological, and genetic features held in common among certain patients with rheumatoid factor-negative polyarthritides, and these were shortly thereafter substantiated by the high association with HLA-B27 (Table 1
). The nosological implication of the plural form of the term spondarthritides (as opposed to spondarthritis) was intended to draw attention to the idea that this was a group of similar and strongly interrelated conditions, rather than a single disease entity with different clinical manifestations. We will return to this point later, in view of the evolving heterogeneous infectious aetiology of, and the high variation in the HLA-B27 association with, the spondarthritides.
This short historical review describing the evolution of the term seronegative arthritis from indicating variants of rheumatoid arthritis to our present understanding of the spondarthritides underlines the following conclusions:
- The term seronegative arthritis still survives and is not completely out of use, which may be illustrated by the fact that the Editor of this journal initially asked us to write this review under the title management of seronegative arthritis.
- The classification and grouping of seronegative arthritis have substantially changed over time.
- Although the concept of spondarthritides is now well accepted world-wide in the rheumatological literature, new insights into the aetiopathology in the future may change our present view.
- Nevertheless, the present classification of seronegative spondarthritis is the best way to help clinicians manage patients having a variety of interrelated clinical presentations and disease manifestations, such as those present in established disease as well as those of the so-called undifferentiated spondyloarthropathies.
The following review will concentrate on recent developments in our understanding of the spondarthritides and will give special attention to data and guidelines which fulfil as far as possible the quality rules of evidence-based medicine (cf. [4]).
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How can we overcome the outdated classification of seronegative arthritis by a rational, cost-effective diagnostic strategy?
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Classifications based on clinical presentation have gradually generated more and more subsets, not only within the older uniform classification as a seronegative arthritis, but also in the new grouping of spondarthritides [5]. Moreover, the spectrum of diseases originally included in the concept has changed (Table 2
). New clinical conditions such as reactive arthritis, juvenile ankylosing spondylitis, seronegative enthesopathic arthropathy syndrome, and undifferentiated spondarthritis are now widely accepted as part of the spectrum, whereas Whipple's disease was excluded due to the discovery of the aetiological agent Tropheryma whippelii. Other conditions such as uveitis, pustolotic arthro-osteitis (SAPHO syndrome), Behçet's disease, and remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) are not generally accepted as part of the concept and do not fulfil all the criteria for seronegative spondarthritides. Finally, for many years we have been familiar with the variety of clinical presentations of idiopathic ankylosing spondylitis. However, with the evolving concept of seronegative spondarthritides, the variety of signs and symptoms and the heterogeneity of presentations, severity, and disease course significantly increased [6]. This is especially true of family studies and follow-up studies of patients with early or abortive disease, which described many cases that did not fulfil the criteria of definite disease.
Therefore, in the years following, the term undifferentiated spondarthritides was introduced as a nosological missing link to classify syndromes failing to meet criteria for definite categories, such as ankylosing spondylitis or psoriatic arthritis [7, 8]. For example, inflammatory back pain and HLA-B27-positive oligoarthritis can be present in some relatives of ankylosing spondylitis patients, and yet they may not show evidence of erosive disease of the sacroiliac joints on radiographic examination. There can be delays of many years before bilateral sacroiliitis appears in radiography. Other manifestations of undifferentiated spondarthritis without radiographic sacroiliitis include inflammatory chest wall involvement, enthesitis, late-onset disease, acute anterior uveitis, and lone aortic regurgitation or complete heart block. Because of this variability and heterogeneity, earlier criteria such as the van der Linden et al. [9] modified New York criteria for ankylosing spondylitis and the preliminary criteria for Reiter's syndrome [10], are valuable for the classification of ankylosing spondylitis or Reiter's syndrome; however, they cannot encompass the full spectrum of the spondylarthritides. Instead, two new sets of classification criteria (Table 3
), the European Spondylarthropathy Study Group (ESSG) criteria and the multiple classification entry criteria diagnosing spondyloarthropathies (Amor criteria) have been proposed with the aim of encompassing the whole clinical spectrum of spondarthropathies, a task both of them fulfil with good sensitivity (ESSG: 75%, Amor: 85%) and specificity (ESSG: 87%, Amor: 90%) [11, 12]. These two sets of criteria, although developed and evaluated for classification purposes, may also be useful in diagnosis, with the limitation that they do not include the full spectrum of diseases, lack the sensitivity to include patients with milder forms [13], and show reduced sensitivity (68%) in the diagnosis of patients with disease duration of less than 1 yr [12]. Nonetheless, one recent study which applied the ESSG criteria in parallel with the American College of Rheumatology (ACR) criteria for rheumatoid arthritis in a cohort of patients with early synovitis (less than 1 yr duration) showed that a considerable number of patients with spondarthritides could be differentiated from patients with early rheumatoid arthritis and undifferentiated arthritis [14].
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TABLE 3. Classification criteria of spondylarthropathies
(A) European Spondylarthropathy Study Group (ESSG) preliminary criteria for the classification of spondylarthropathies (B) Amor criteria for the classification of spondarthritides
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A major advantage of the ESSG and the Amor criteria is their feasibility, which allows cost-effective classification and diagnosis. Their high sensitivity and specificity are achieved mainly by use of clinical items. The content of each criteria set is overlapping, the Amor set using 12 instead of the nine criteria of the ESSG set. The ESSG two-entry criteria are fulfilled only in patients with inflammatory spinal pain and/or asymmetrical synovitis, predominantly of the lower limb, together with at least one of the following: family history positivity, psoriasis, inflammatory bowel disease, enthesopathic lesions, or radiological sacroiliitis. Importantly for the clinician in everyday practice, the Amor multiple-entry criteria credit all relevant clinical presentations and additionally include sausage-like toe or digit, iritis, non-gonococcal urethritis or cervicitis, acute diarrhoea, HLA-B27, and the response to treatment with non-steroidal anti-inflammatory drugs (NSAIDs). Moreover, the Amor criteria are based on a weighted point scale, and a patient is considered as suffering from spondarthritis if the sum of the 12 criteria values is at least 6 points. In summary, the ESSG criteria are shorter and easier to perform especially in epidemiological studies, but the Amor criteria are comprehensive and adapted to clinical variance; thus, they are more accurate and perform better. With the increasing identification of bacterial components in the joint by modern molecular techniques, it will be necessary to develop additional criteria to include different infectious aetiologies.
The only technical information included in the new sets of criteria are HLA-B27 typing (Amor criteria) and radiological examination of the sacroiliac joint (Amor and ESSG criteria). In general, little additional useful information is derived from routinely typing patients with classical ankylosing spondylitis for HLA-B27 [15]. However, in mono- or oligosymptomatic diseases such as peripheral arthritis, enthesitis, dactylitis, acute anterior uveitis, or atrioventricular conduction block, HLA-B27 typing may be useful for early diagnosis of undifferentiated spondarthritis [16, 17]. Furthermore, HLA-B27 typing is valuable with regard to prognosis. HLA-B27-negative patients with reactive arthritis have a good prognosis and do not develop spondylitis, whereas HLA-B27-positive patients tend to develop chronic disease with spine involvement [18].
Serological studies of antibacterial antibodies, the identification of bacteria-specific T-cells in the inflamed joint, and, ultimately, modern biological testing of synovial specimens have increasingly identified and defined bacterial causes for joint disease in patients diagnosed initially with undifferentiated arthritis or undifferentiated spondarthritis according to the ESSG criteria (cf. [19]). The aetiological diagnosis of reactive arthritis requires the demonstration of recent or ongoing infection with a causative bacterium. This may be satisfied by serological demonstration of antibacterial antibodies, diagnosis of extra-articular infection, or preferably by the identification of the causative agent in joint specimens using molecular techniques.
Although serology may indicate recent or persistent infection, the high prevalence of certain antibacterial antibodies, and the persistence of antibodies even after cure of the infection, underscore the severe limitations of serological diagnosis of reactive arthritis. In case of recent organ symptoms suggestive of bacterial infection, specific serology is warranted. In this regard, positive serology both for IgG and IgA may indicate an acute or persistent infection.
With regard to the diagnosis of extra-articular infection, it should be stressed that even in the absence of clinical signs of urogenital tract (UGT) infection, Chlamydia can be demonstrated in UGT specimens in at least one-third of patients with Chlamydia-induced arthritis [20]. We therefore recommend analysis, for example, of first void urine for UGT infection in undifferentiated arthritis patients using ligase chain reaction. In post-dysenteric reactive arthritis, however, a search for the triggering micro-organism in faeces is only useful in the case of positive serology or persisting dysenteric symptoms.
Molecular biological techniques such as the polymerase chain reaction (PCR) are being used increasingly to detect the triggering organism in joint specimens [21]. Due to their enormous sensitivity and their ease of use, it is conceivable that these techniques will become the methods of choice in the future for routine diagnosis of reactive arthritis [22]. However, the standardization of these techniques is needed urgently to allow for their more widespread use in clinical laboratory practice.
For many years, conventional radiography was the mainstay for definitive diagnosis of sacroiliitis, and for follow-up of the anatomical changes in the spine, joints, and enthesis. However, computer-assisted tomography (CT), bone scintigraphy, single-photon emission computer tomography (SPECT), and most recently magnetic resonance imaging (MRI) as well as sonography have improved early diagnosis [2325]. In addition they have also enabled more accurate detection of pathology at various anatomical sites of the musculoskeletal system predominantly involved in spondarthritides. The finding of prominent entheseal abnormalities on MRI as a consistent feature of new-onset synovitis may have important implications for the diagnosis, classification, and mechanisms of synovitis in patients with spondarthritis [26].
Compared with radiography, these new imaging techniques have the general advantages that: (1) they allow early diagnosis of sacroiliitis in the radiographically normal or equivocal stage, and (2) they allow better identification of the severity and distribution of inflammatory changes, in contrast to the resulting process of destruction and ankylosis identified by conventional radiography. Moreover, serial plane films and CT scanning involve the highest exposure to radiation. Bone scintigraphy exposes patients to less radiation, but many studies have questioned its sensitivity and specificity for the detection of sacroiliitis. On the other hand, this imaging technique has practical importance in patients with multilocular inflammatory manifestations in the spine, joints, and enthesis, especially at locations difficult to investigate by clinical examination, such as intervertebral discs, apophyseal joints, costovertebral and costotransversal joints, anterior chest wall, symphysis, and enthesial sites.
Various recent studies have convincingly shown that MRI is the most sensitive method for the identification of active sacroiliitis in established as well as early or undifferentiated spondarthritis [2325, 27]. Since chronic sacroiliitis is accompanied by peri-articular fat accumulation, the use of the fat suppression technique in MRI of the sacroiliac joint may be required to differentiate between fat and oedema [25]. The latter is a hallmark of an active inflammatory process. Nevertheless, one must also realize the limitations of MRI. In patients with well-advanced sacroiliitis and less or absent active inflammation, MRI is not more effective than other imaging techniques.
From such evidence established by clinical research, each practitioner must draw his/her own conclusions and use the new imaging techniques as he/she sees fit in the diagnosis of sacroiliitis. To our knowledge, no systemic study has evaluated the differential and stepwise use of different imaging techniques for the diagnosis of sacroiliitis. Therefore, we present our own individual strategy, which we are using currently in our clinic. In any patient with inflammatory low back pain or suspected spondarthritis, we begin with an anteriorposterior and lateral plane film of the lumbar spine, including the sacroiliac joints and the dorso-lumbar junction. The next step depends on the outcome of this radiograph. In the case of grade 24 sacroiliitis, no further imaging is required. In the case of equivocal grade 1 sacroiliitis, we first use CT, except for young adults or young females to avoid radiation exposure, where we prefer to use MRI. If these imaging techniques give no definite and unequivocal result, then scintigraphy and SPECT are the next choices for imaging. Finally, in the case of a normal radiograph we use MRI directly, except in those patients where a multilocular involvement indicates the preferential use of scintigraphy plus SPECT; this enhances the chances of discovering the inflammation at different sites of the musculoskeletal system with one procedure.
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Which follow-up measurements are really needed for routine management?
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Over 100 assessments of outcome for use in ankylosing spondylitis have been described in the literature, but most of the measures employed were not standardized [28]. Many methods exist to assess spinal mobility, and even for the Schober index there are several ways to perform the test. For a long time there was no consensus on a core set of variables and endpoints to measure in routine management. Therefore a group of experts, the International Assessments in Ankylosing Spondylitis (ASAS) working group, organized several meetings to propose recommendations for measures of outcome to be used in various settings. This ASAS group works under the auspices of International League Against Rheumatism and collaborates with OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical trials). The group decided to define core sets for clinical record keeping, physical therapy, symptom-modifying anti-rheumatic drugs, and disease-controlling anti-rheumatic therapy. During several workshops, a consensus approach in nominal group discussions and plenary sessions was used to reduce the number of possible measures to a meaningful selection of specific variables, based on aspects of feasibility and relevance. Using statistical cluster analysis of a controlled drug trial, Calin et al. [29] identified relevant domains and measurements sensitive to change under NSAID treatment. Following these proposals, rheumatologists world-wide now may start to include these measurements in everyday clinical management of ankylosis spondylitis and other spondarthritides with spinal involvement (Table 4
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A core set of data should be obtained from the patient at each visit. This includes history since the last visit, physical examination, laboratory tests, and, if required, imaging studies. The follow-up should enable the rheumatologist to judge the course as well as the activity of the disease, and thus serve as a rational basis for therapeutic decision-making. According to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) the patient should be asked about global assessment, the level of fatigue, inflammatory back pain, spinal stiffness/mobility and peripheral joint/entheses involvement [29]. Further, the efficacy as well as the side-effects of therapy should be recorded. The physical examination should include spinal mobility, Schober index, chest expansion, occiput-to-wall distance, and Mennell's sign. Further, the assessment of peripheral joints according to the core set for rheumatoid arthritis and painful enthesis must be recorded [31].
The clinical relevance of acute-phase reactants in ankylosing spondylitis is not well established because acute-phase reactants do not comprehensively represent the disease process [32]. Levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) tend to be lower compared with those in rheumatoid arthritis, and they vary only to some degree with changes in disease activity. ESR and CRP correlate well with the clinical manifestation of peripheral joint involvement. Comparing both ESR and CRP, neither measure is clearly superior on the basis of currently existing data [33]. Feasibility aspects favour ESR in terms of lower cost, ease of performance, standardization of test, and promptness of result. Drug therapy should be monitored according to the recommendations of the ACR guidelines for rheumatoid arthritis [34].
As outlined above, imaging techniques are of major importance in the establishment of sacroiliitis and to sustain the diagnosis of spondarthritis; however, they are rarely required for follow-up [35]. A simple radiological scoring system for the spine in patients with ankylosing spondylitis has been evaluated as a reliable method for grading radiographic changes [36]. This new instrument, the Bath Ankylosing Spondylitis Radiology Index (BASRI) is of great importance with respect to clinical trials investigating disease-modifying drugs (DMARDs) and may in the future also be of value for everyday practice.
New or altered symptoms should raise a concern of disease progression or complications, such as spinal fractures and spondylodiscitis. In the latter case, a stepwise procedure is warranted starting with plain radiographs, and, if needed, technetium isotope scanning and/or MRI.
Erosive joint disease is not a common feature of spondarthritis, except in psoriasis arthritis. Since the kinetics of radiographic progression of erosive peripheral arthritis in spondarthitides is unknown, in this disease repeated radiographs may be obtained similar to those used for monitoring in rheumatoid arthritis [37]. Ultrasound of inflamed joints may reveal thickening of the synovial membrane and is helpful in arthrocentesis of small joint effusions.
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Symptom- and problem-orientated therapeutic management
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The main objectives of therapeutic management of ankylosing spondylitis and other spondarthritides are patient education, physical therapy to restore and maintain posture and movement, self-management with exercise, and, most importantly, relief of pain and stiffness to facilitate physical therapy. To achieve these goals a comprehensive therapeutic approach is necessary. The selection and combination of therapeutic options, such as physical treatment, drug therapy, and surgical therapy, depend on activity and the stage of the disease (Table 5
) (cf. [4, 38, 39]).
Spinal disease
Physical therapy and NSAIDs are the cornerstones of treatment of axial involvement. Initially, the most common NSAIDs in use for ankylosing spondylitis were phenylbutazone and then indomethacin, but many others have been shown to be effective, including diclofenac, naproxen, piroxicam, and most recently meloxicam [4, 40]. It is not known whether continuous treatment has long-term advantages over intermittent therapy. Reduced ossification has been suggested after prolonged and continuous use of phenylbutazone [41].
A study from Amor and colleagues has convincingly shown that the efficacy of NSAIDs can be defined by clear-cut improvement in pain and morning stiffness within 48 h, or relapse within 48 h after discontinuing the drug [11]. In the case of inefficacy, one should change from one drug to another, especially to more potent NSAIDs such as indomethacin or phenylbutazone. A very recent double-blind, placebo-controlled study comparing piroxicam with two doses of meloxicam showed that the optimum duration of a NSAID drug trial is 1 yr rather than the usual 6 weeks. Over such a long time differences in efficacy and tolerance will become more obvious [40]. The discontinuation rate after 1 yr favoured meloxicam 22.5 mg over meloxicam 15 mg and piroxicam 20 mg.
A general statement of many reviews and textbooks is that analgesics or corticosteroids are seldom needed. However, recent observations have indicated that nearly 30% of patients with ankylosing spondylitis take analgesics [42]. In moderately or severely active disease the rate is even higher, and even more importantly patients treated by rheumatologists use analgesics in nearly 50% of cases, with a rate of 38% of narcotic analgesics. If one looks in the literature, these data are in good accordance with earlier reports [43]. Therefore, we must conclude that in a considerable number of patients our present management using NSAIDs is not nearly effective enough to fulfil the objective of pain relief. We must look for more effective anti-inflammatory treatments in many cases.
A beneficial effect of intra-articular glucocorticoids has been demonstrated in cases of refractory low back pain due to sacroiliitis [44, 45]. Most recently, it has been shown that peri-articular glucocorticoid treatment of the sacroiliac joint provides significant improvement [46]. Oral glucocorticoid therapy is of little if any use in the treatment of spine involvement, but pulse methylprednisolone therapy may be used occasionally in severe NSAID-resistant acute flares. Two open studies and two dose-regime comparative studies showed a dramatic improvement in morning stiffness, back pain, and spinal mobility [4750]. Improvement was maximal at 1 week and was maintained for 321 months. Three to four pulses gave a more prolonged improvement than did one or two pulses, but the doses of 1 g prednisolone equivalent was not more effective than 375 mg [47, 50]. If the anti-inflammatory therapy fails to control spinal pain, the additional use of analgesics (paracetamol, dextroprooxyphene, opoids) and/or amitriptyline (30 mg daily) [51] is indicated to improve pain, sleep, and mobility.
Whether second-line drugs alter the course of spinal disease has not been clarified unequivocally. Placebo-controlled trials are available only for sulphasalazine but did not show a consistently favourable effect compared with placebo [52, 53]. In clinical practice, sulphasalazine can only be proposed for selected patients with refractory axial involvement, especially in early disease as one treatment option. The efficacy of this therapy should be evaluated after 4 months.
Enthesiopathy
Enthesitis is a hallmark of spondarthritis. The degree of pain can vary from mild to disabling. Therapy of enthesitis consists of NSAIDs, physical therapy, and orthoses [54]. If disease is refractory to this therapy, local steroid injections should be tried. Conflicting data exist with respect to the use of sulphasalazine as a second-line drug [55, 56]. Therefore, treatment with sulphasalazine is only recommended after failure of the therapeutic options mentioned above. Low-dose anti-inflammatory radiotherapy is reserved for those patients with persistent enthesitis despite physiotherapy and appropriate drug treatment [57].
Peripheral arthritis
The indication of the different therapeutic modalities is based on the extent of the articular involvement and the duration of the symptoms. NSAIDs are effective in the therapy of arthritis. Acute flares can be treated with intra-articular or systemic glucocorticoids. DMARDs are indicated for persisting symptoms of at least 3 months, erosive joint disease, or recurrent flares. Several studies suggest that sulphasalazine is well tolerated and effective in patients with peripheral joint disease [52, 53, 58, 59]. Little information is available for other DMARDs [4]. Methotrexate is used by rheumatologists in up to 1113% of patients with moderately or severely active ankylosing spondylitis [42], but more recent open studies provide only circumstantial or no evidence of the efficacy of methotrexate therapy [60, 61]. Therefore, further clinical studies are required before methotrexate can be considered as an established therapy [62].
Underlying chronic or persistent infections
The contention that reactive arthritis belongs to the group of spondarthritides is based on several lines of evidence. The clinical spectrum of reactive arthritis frequently includes sacroiliitis and enthesitis, features observed in ankylosing spondylitis and other spondarthropathies. Reactive arthritis is associated with the HLA-B27 allele, although the degree of association varies with the specific causative agent [63, 64]. Moreover, in ankylosing spondylitis an increased rate of UGT infection and chronic prostatitis has been observed [65].
Reactive arthritis is characterized by the presence of bacteria or bacterial macromolecules in the synovial fluid or membrane, although microbial pathogens cannot be cultured from synovial material. Bacteria known to trigger reactive arthritis include Campylobacter, Chlamydia, Salmonella, Shigella, and Yersinia [63, 66]. The continued synthesis of bacterial antigens to maintain synovial inflammation probably requires the establishment of persistent bacterial infection of the joint, or at the primary site of infection with subsequent distribution of antigens into the joint [63, 67]. A therapy resulting in the eradication of bacteria should cure the disease. However, in controlled studies no effect favouring the prolonged use of antibiotics for reactive arthritis has been found [39, 67]. The lack of efficacy of antibiotics may be related to the altered metabolic state of the organisms at issue. At present, long-term antibiotic therapy should be evaluated in clinical trials.
Management of refractory spondarthritides
Refractory spondarthritis can be defined as the presence of a persistent complaint of rheumatic symptoms despite an optimal intake of NSAIDs [56]. Before classifying a patient with generalized spondarthritis refractory to NSAIDs, the dose of the NSAID should be increased to the maximum. Further, a change from one NSAID to another should be considered. Phenylbutazone is the most effective NSAID for treating spondarthritides. In case of treatment failure of the standard NSAIDs, the benefitrisk ratio favours the use of this compound in a daily oral dose of 400600 mg. Close monitoring is required to recognize potentially severe toxicity, such as agranulocytosis.
When NSAIDs are ineffective, pulse therapy with intravenous methylprednisolone 15 mg/kg for 3 days may rapidly control the acute flares [49]. In case of sustained disease activity over more than 3 months, sulphasalazine may be tried for refractory axial and/or peripheral joint involvement to influence the cause of chronic disease. The clinical effect of sulphasalazine begins after 48 weeks of treatment, and maximal benefit is achieved after 1216 weeks of treatment. Therefore, this drug must be taken for at least 4 months before a decision about its efficacy can finally be made.
For those patients who still have complaints despite this stepwise approach, experimental drugs, such as bisphosphonates, with potential benefit in spondarthritis can be tried (see below).
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Future perspectives
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As mentioned earlier, NSAIDs are the cornerstone of therapy for the spondarthritides. However, NSAIDs can cause clinically important side-effects, especially in the gastrointestinal tract. Risk stratification, as well as the use of preventive strategies to minimize serious complications such as gastrointestinal bleeding and perforation, have been discussed in detail [68, 69]. Increasing evidence suggests that a new class of NSAIDs, the cyclooxygenase-2-specific inhibitors, have no deleterious effect on the gastrointestinal tract. The value of cyclooxygenase-2 inhibitors in the anti-inflammatory therapy of spondarthritides, and their potency to relieve pain compared with conventional NSAIDs such as indomethacin, remains to be established. Further, the duration of the NSAID therapy, e.g. continuous vs intermittent, is an open question (see above). We recommend intermittent use according to symptoms and activity until clear evidence has established the superiority and safety of continuous treatment. Physical therapy modalities are an integral part of the management of ankylosing spondylitis. The aims of physiotherapy are to improve mobility and strength, and to prevent stiffness and deformities [70, 71]. NSAIDs are often required for the control of inflammation and pain relief to enable physiotherapy. Therefore, such medication can be stopped if the patient is free of pain and able to perform physiotherapy on a daily basis.
Therapeutic modalities for slowing progression and preventing ankylosis are urgently needed. These may include the development of new drugs and the evaluation of drugs which have shown a beneficial effect in other diseases. In a pilot study, intravenous application of pamidronate showed significant anti-inflammatory activity [72]. Biological response modifiers such as anti-tumour necrosis factor (TNF) antibodies or thalidomide [73] are currently being evaluated for their efficacy in the treatment of spondarthritides.
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Conclusions
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The concept of an interrelated group of disorders termed spondarthritides is now well accepted for the classification, diagnosis, and therapeutic management of a high proportion of individuals with inflammatory rheumatic conditions. The development of classification criteria, major advances in imaging techniques, and the formulation of valuable outcome measurements are important steps towards an earlier and more rational treatment of this group of diseases. Further, the spectrum of therapeutic modalities useful in clinical practice has been enlarged meaningfully. However, we are far from being able to control the disease in all patients, especially those with severe manifestations and course. In applying the recommendations of evidence-based medicine, one must be aware that for many therapies only limited data are available, and many of our decisions are therefore experientially and clinically based. Future efforts to advance therapeutic management should specifically address the issues of disease-modifying agents and of slowing bone ankylosis, as well as elucidating the possible infectious aetiologies of spondarthrides to empower a causative therapy.
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Acknowledgments
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The authors thank Dr A. P. Hudson for the critical reading of the manuscript. Our work is supported by DFG KU1182/I-I and 13; BMBF 01VM9305; Deutsche Stiftung für Herzforschung; Gesellschaft der Freunde der Medizinischen Hochschule Hannover; BIOMED BMH4-CT-983605.
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Notes
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Correspondence to: H. Zeidler. 
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Submitted 8 October 1999;
revised version accepted 23 November 1999.