Dear Editor,

Sieper et al. evaluated whether combination therapy with Infliximab (IFX) and naproxen (NPX) was superior to treatment with NPX alone in patients who had active moderate-to-severe early (disease duration under 3 years) active axial spondyloarthritis (SpA) and who were naive to nonsteroidal anti-inflammatory drugs (NSAIDs) or had only been treated with a submaximal dose of NSAIDs (1). This study is the first investigation of the potential benefits of early TNF-antagonist treatment in active axial SpA patients who are not yet refractory to NSAID therapy. Additionally, this represents the first randomised controlled clinical trial to use the imaging portion of the Assessment of SpondyloArthritis International Society (ASAS) criteria for axial SpA with active inflammation of the SI joints on MRI at baseline. Most importantly, the evidence from this study supports early diagnosis and treatment of SpA with a full dose of NSAIDs first, escalating to combination NSAID+TNF antagonist treatment in patients who have insufficient response.
Moreover, this study provides important insights about the application of the new classification criteria for axial SpA in a clinical trial.
Approximately 60 % of patients had ankylosing spondylitis (AS) fulfilling the modified New York radiographic criteria. Thus 40% of patients had nonradiographic axial SpA classified by MRI; it would be of interest to know if in these patients the additional SpA features for classification were different from AS patients. Arthritis was quite often in both treatment arms (45.3% vs 26.9%, respectively). Importantly, the 66- joint swollen joint count and 68- joint tender joint count was ameliorated considerably in both treatment arms and significantly better for swollen joints with NSAID+TNF antagonist treatment. Also in other studies testing adalimumab against placebo and etanercept against sulfasalazine, respectively, arthritis was found in 29% up to 52% of patients with early axial SpA (2, 3, 4). Evidently, simultaneous peripheral symptoms are frequent in nonradiographic and early axial SpA.
This raises the question if future studies should include together patients fulfilling the axial and/or peripheral SpA criteria to establish treatment evidences for SpA in general; thus would be possible to promote approval of established and new treatments for most conditions unified under the umbrella of SpA instead of testing for each individual diagnosis and subgroup of clinical manifestations. However, this requires more attention to infections associated with reactive arthritis which have been included in the criteria for peripheral but not for axial SpA (5, 6, 7).
Preceding infection (balanitis, urethritis, cervicitis and/or acute diarrhea) is noted in 37% of patients with peripheral SpA (8). Furthermore 35% of the patients with peripheral SpA have radiographic sacroiliitis (8). This overlap between axial and peripheral symptoms demonstrates that the construct of separating SpA into predominant clinical manifestations is somewhat artificial and only partially reflect the clinical reality given the heterogeneous character and fluctuating course of the diseases belonging to the SpA concept. Especially in the early years of the disease, the main target of the new classification criteria, AS progresses by a series of flares involving localized area such as the knee, neck, ankle, or localized area of the back (9, 10, 11). Many patients with SpA at some time of the disease can have either prominent peripheral and axial symptoms concurrently or peripheral and axial symptoms successively. The classification may change from axial to peripheral and vice versa at different times in a given study, compromising the consistency of classification in long-term trials. Finally, the description of increased frequency of Chlamydia-positive synovial tissue samples in patients with chronic undifferentiated SpA, the growing insight into the etiology of persistent chlamydial infection, and the promising treatment of Chlamydia- induced arthritis with combination antibiotic therapy indicate the necessity of further splitting SpA into underlying disease entities such as reactive arthritis (c. f. 12).

References

1. Sieper J, Lenaerts J, Wollenhaupt J, et al. Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo- controlled INFAST study, Part 1. Ann Rheum Dis Published Online First: [21 May 2013] doi:10.1136/annrheumdis-2012-203201

2. Sieper J, van der Heijde D, Dougados M et al. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 2013;72:815-22.

3. Haibel H, Rudwaleit M, Listing J, et al. Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo- controlled trial followed by an open-label extension up to week fifty-two. Arthritis Rheum 2008;58:1981-91.

4. Song IH, Hermann K, Haibel H et al. Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial. Ann Rheum Dis 2011;70:590-6.

5. Rudwaleit M, van der Heijde D, Landew? R, et al. The Assessment of SpondyloArthritis international Society (ASAS) Classification Criteria for peripheral Spondyloarthritis and for Spondyloarthritis in general. Ann Rheum Dis 2011;70:15-21.

6. Zeidler H, Amor B. The Assessment in Spondyloarthritis International Society (ASAS) classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general: the spondyloarthritis concept in progress. Ann Rheum Dis 2011;70:1-3.

7. Zeidler H. The historical concept of interrelated conditions lumped together as a family of distinct diseases is not outdated. Arthritis Rheum 2013;65:2214-5.

8. van den Berg R, van Gaalen F, van der Helm-van Mil A, Huizinga T, van der Heijde D. Performance of classification criteria for peripheral spondyloarthritis and psoriatic arthritis in the Leiden Early Arthritis cohort. Ann Rheum Dis 2012;71:1366-9.

9. Wilkinson M, Bywaters EG. Clinical features and course of ankylosing spondylitis; as seen in a follow-up of 222 hospital referred cases. Ann Rheum Dis 1958;17:209-28.

10. Brophy S, Calin A. Definition of disease flare in ankylosing spondylitis: the patients' perspective. J Rheumatol 2002;29:954-8.

11. Stone MA, Pomeroy E, Keat A et al. Assessment of the impact of flares in ankylosing spondylitis disease activity using the Flare Illustration. Rheumatology 2008;47:1213-8.

12. Zeidler H, Hudson AP. New insights into Chlamydia and arthritis. Promise of a cure? Ann Rheum Dis 2013 (in press).

Conflict of Interest:

None declared

Dear Editor,

We have read the letter by Bossuyt X. and Fieuws S. entitled "Detection of anti-nuclear antibodies, added-value of solid phase assay?" with great interest (1). In this letter the authors described a comparison between anti-nuclear antibodies (ANA) performed by indirect immunofluorescent assay(IIFA) and by an automated method (fluoroenzymeimmunoassay; EliA CTD screen, Thermo Fisher) using samples obtained from patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc),Sj?gren's syndrome (SS) and healthy controls. The authors concluded that the favorable method for ANA detection is disease-dependent and that combining IIFA with solid phase assay can increase the diagnostic accuracy. These points, raised by Bossuyt X. and Fieuws S., may be regarded in the perspective of the international recommendations for ANA detection that we have recently published (2). Indeed, our recommendations support the use of IIFA as well as alternative methods (such as EliA) to determine antibodies of the ANA family, even stating that these new methods may represent the future of autoimmune diagnostics. However, it should be noted that, unlike most new methods, IIFA enables detection of numerous cellular antigens. Furthermore, diagnostic/classification criteria of several autoimmune diseases, like SLE, autoimmune hepatitis and juvenile idiopathic arthritis, are based on ANA results obtained by IIFA. Thus, for screening purposes, especially as laboratory personnel are usually unaware of the suspected diagnosis, IIFA should remain the reference method. On the other hand we (2) have highlighted the limitations of IIFA and acknowledged, similarly to Bossuyt X. and Fieuws S., that certain methods may be easier to perform and even more sensitive than IIFA regarding a specific autoimmune disease, for instance SS or inflammatory myopathies. However, this should be evaluated for each method regarding each autoimmune disease and addressing different populations. More importantly, information regarding each alternative method should be clearly communicated with the requesting physician (i.e. method of choice and test characteristics for the respective autoimmune diseases) to avoid erroneous application of IIFA test characteristics to these alternative methods.

The issue of using multiple screening tests has been raised by us and by others. We believe that this may significantly improve the accuracy of autoimmune diagnostics, but it requires a sophisticated algorithm for interpretation of discrepant results. Moreover, it is highly unlikely to be cost-effective and most likely is in conflict with most national reimbursement policies.

Notably, most requests for ANA testing are issued by general practitioners and non-rheumatologists/immunologists and in many cases this is done in the context of diagnosing a wide array of conditions (3). Given the poor specificity of ANA testing by IIFA, it can be argued that in particular ANA requests for patients with a low pre-test probability solid-phase assays may be preferred (4). We agree with Bossuyt X. and Fieuws S. that different diseases do require different approaches and we have recently dealt with the issue of multiple testing algorithms for distinct autoimmune conditions as specified in Fig. 1 (5). Furthermore, in our international recommendations (2) we highly supported the addition of laboratory comments that will specify further options. For instance, adding a comment such as "If clinical suspicion of SS is high, further studies using an alternative method such as EliA should be considered" may guide the physician to request the additional tests in a much more restricted way. Again, this underscores the importance of bidirectional communication: i.e. clinical information enables appropriate choices in the laboratory and laboratory comments direct appropriate add-on testing to be requested by the physician.

Figure see the monthly ePage for Annals of the Rheumatic Diseases

References

1. Bossuyt X and Fieuws S. "Detection of anti-nuclear antibodies, added- value of solid phase assay?" Current Issue.

2. Agmon-Levin N, Damoiseaux J, Kallenberg C, et al. International recommendationsfor the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis 2013 Oct 14.

3. Mahler M, Hanly JG, Fritzler MJ. Importance of the dense fine speckled pattern on HEp-2 cells and anti-DFS70 antibodies for the diagnosis of systemic autoimmune diseases. Autoimmun Rev 2012;11(9):642-5.

4. Abeles AM, Abeles M. The clinical utility of a positive antinuclear antibody test result. Am J Med 2013;126:342-348.

5. Damoiseaux JandAgmon-Levin N. Anti-Nuclear Antibodies: a long way to harmonization. In: Infections, Tumors and Autoimmunity (Eds: Conrad K, Chen EKL, Fritzler RL et al.), Autoantigens, Autoantibodies, Autoimmunity 2013;9:284-289 (E-book).

Conflict of Interest:

None declared

Dear editor,

We thank Forestier and Erol for their response on our paper on Eular recommendations for the non-pharmacological core management of hip and knee osteoarthritis (OA). We agree that balneotherapy is a relevant non- pharmacological intervention in hip and knee OA, and has been properly evaluated by means of randomised clinical trials, with the evidence summarized in systematic reviews. The topics to be included in the recommendations were however, in accordance with the standard operating procedures for the development of Eular recommendations [1], determined by the Task Force. Starting with a long list of propositions on a wide range of non-pharmacological interventions, the final set was selected by means of several Delphi rounds. This procedure resulted, apart from the exclusion of balneotherapy, in the omission of several other non- pharmacological interventions which are relevant and for which evidence is available.
The process of development of the recommendations does not include a registration of reasons for selection and exclusion of propositions, however specifically for balneotherapy it could be hypothesized that this intervention is not equally available and/or common in every country.
In general terms, the issue Forestier raises is important from the implementation perspective. It remains to be established to what extent the selection of topics plays a role in the uptake of the recommendations. The exclusion of recommendations on topics which are considered relevant in clinical practice, and likewise the inclusion of recommendations on topics which are not supported by clinicians may play an important role in the implementation. A study on barriers and facilitators for the implementation of recommendations among various groups of stakeholders is needed to further study this aspect. The outcome of such a study may not only influence the content of an update of the current set of recommendations, but probably also the process of guideline development as a whole, with probably larger groups of people in the various stakeholder groups being needed to select the topics to be included in the recommendations.

References

1. Dougados M, Betteridge N, Burmester GR et al. EULAR standardised operating procedures for the elaboration, evaluation, dissemination, and implementation of recommendations endorsed by the EULAR standing committees. Ann Rheum Dis 2004;63:1172-6

Conflict of Interest:

None declared

Dear Editor,

We appreciate that EULAR is preparing a specific recommendation on non-pharmacological treatment of knee osteoarthritis but we are also very surprised to discover that crenobalneotherapy was not even mentionned in the analysed treatments. Crenobalneotherapy (also called balneotherapy or spa therapy) is a very common treatment for knee osteoarthritis in South and Eastern Europe, Middle Asia, Japan, South America and North Africa. The common point of crenobalneotherapy procedures is the use of mineral water for the treatment. While, it can sometimes be a passive bath only, more often it is a combined treatment with underwater massages, mud applications, water exercises, baths and showers. We think that crenobalneotherapy is a non- pharmacological treatment.
In 2008, we conducted a systematic review [1] and we concluded that "although the consistency of the results suggests a therapeutic effect of crenobalneotherapy in limb osteoarthritis, available studies are methodologically inadequate and sample sizes too small to allow definitive conclusions". Later, in 2010 we published a multicenter randomized trial on 462 patients suffering from knee osteoarthritis in Annals of Rheumatic Diseases [2]. The results showed a clinically important improvement in pain and function for the balneotherapy group when compared with the control group doing home exercise alone. We suggest that, since crenobalneotherapy is a well evaluated treatment, these non- pharmacological treatment guidelines should also analyse this and some other trials published in this field [3-4].

References

1. R Forestier, A Francon. Crenobalneotherapy for limb osteoarthritis: systematic literature review and methodological analysis. Joint Bone Spine 2008 ;75(2):138-48.

2. Forestier R, Desfour H, Tessier JM, et al. Spa therapy in the treatment of knee osteoarthritis: a large randomised multicentre trial. Ann Rheum Dis. 2010;69(4):660-5.

3. Fioravanti A, Iacoponi F, Bellisai B, et al. Short-and long-term effects of spa therapy in knee osteoarthritis. Am J Phys Med Rehabil 2010;89(2):125-32.

4. Nguyen M, Revel M, Dougados M. Prolonged effects of 3 week therapy in a spa resort on lumbar spine, knee and hip osteoarthritis: follow-up after 6 months. A randomized controlled trial. Br J Rheumatol 1997;36(1):77-81.

Conflict of Interest:

None declared