Dear Sir,

As the use of anti-tumor necrosis factor α (anti-TNFα) treatment has grown, the increasing incidence of associated infectious complications, particularly tuberculosis, has emerged as the therapy’s main drawback.[1] Currently, screening for tuberculosis prior to initiation of treatment with anti-TNFα agents relies on clinical and radiographic assessment and the tuberculin skin test (TST).[2] In case of latent infection, a course of chemoprophylaxis with one of the accepted regimens should be instituted to prevent development of active disease due to exposure to anti-TNFα.[2,3,4]

Some interesting recent reports have focused on the prevention of tuberculosis in these patients. However, they may cause some misunderstanding, especially among physicians who are not used to dealing with the problem. [3,5,6) Firstly, it has been suggested that the TST is not helpful in patients receiving immunosuppressive therapy and therefore should not be performed;[3,5] secondly, based on the observation that some patients with initial negative TST become positive in the course of anti- TNFα therapy, another report recommends repeating the test after certain period of treatment.[6]

The latest guidelines of the British Thoracic Society (BTS) question the usefulness of the TST in patients on immunosuppressant treatment.[3] Given the test’s unreliability in patients receiving an immunosuppressive agent that is the majority, the guidelines argue against its use. The strategy they propose involves calculating the individual annual risk of tuberculous infection on the basis of clinical and epidemiological data such as age, ethnic group, and length of time in the developed country.[3,5] While accepting that the sensitivity of the TST in these circumstances is indeed lower with the impaired delayed-type hypersensitivity (DTH) due to the treatment or the disease itself,[7] it should be borne in mind that the clear decline in the incidence of active tuberculosis among patients receiving anti-TNFα has been achieved with the implementation of programs for detection and prevention of reactivation of latent disease, based mainly on the TST and chemoprophylaxis with isoniazid.[2-4] In addition, the critical level of immunosuppression above which the TST is not reliable for estimating the likelihood of anergy in a particular individual receiving immunosuppressive drugs is unknown at present.

In another report published in this journal,[6] Joven BE et al. prospectively studied 61 patients with rheumatic disease, mostly rheumatoid arthritis, treated with infliximab. Interestingly, after 54 weeks of treatment, 3 of 48 (6.3%) patients with initially negative TST became positive, and 1 of 13 (7.6%) positive at initial TST became negative. What is more, in patients with positive initial TST, the mean induration diameter increased. The authors concluded that antiTNFα agents, rather than interfering with the cellular immune response to mycobacterial antigens, can actually improve the diagnostic value of the TST by improving the anergy associated with active arthritis. They suggest repeating TST in patients with an initial negative test after a period with anti-TNFα treatment.

In our opinion, the findings of that study do not really demonstrate a role for anti-TNFα in the reversion of the anergy associated with rheumatoid arthritis by control of the active disease. Firstly, the change in the TST reactivity status after 54 weeks of treatment may be due merely to the enhancement of the DTH produced by the second TST in a previously infected or BCG-vaccinated subject with an attenuated response to the purified protein derivative (PPD) (the booster effect). In the Tuberculosis Unit at our institution, in which a two-step TST is routinely performed in all candidates for anti-TNFα over the age of 55, vaccinated with BCG and those on immunosuppressive treatment, 15% (with a 15.9% of vaccinated patients) of individuals with initial negative TST resulted positive in the second test 7 days later, indicating a past infection. In the study by Joven BE et al., the two-step TST was not carried out and no data on BCG vaccination were provided. Secondly, even without a recognizable contact, a “de novo” infection cannot be ruled out, especially in a country like Spain with a moderate incidence of active disease (25 cases/105).[8] Thirdly, according to one study, response to PPD was found not to be influenced by disease activity.[3] Finally, one out of the three patients in the study who changed from negative to positive had ankylosing spondylitis, a rheumatic disease that has not ever been associated with any kind of immunosuppression. So, although anti- TNFα therapy may in fact reverse the attenuated response to PPD in these patients by controlling the disease activity, more studies are needed to establish the real influence of these agents on the immune response to mycobacterial antigens.

In summary, with the data available at present, we recommend performing TST in candidates for anti-TNα therapy in order to detect latent tuberculous infection, regardless of whether they are receiving immunosuppressive treatment. We also advocate the two-step TST in immunosuppressed patients with a negative first test. The TST in patients receiving anti-TNFα treatment, should be repeated only in appropriate clinical circumstances.

Finally, the new diagnostic methods based on the detection of gamma- IFN production after stimulation with Mycobacterium tuberculosis-specific antigens (ESAT6 and CFP 10), by ELISA or ELISPOT techniques, may facilitate the assessment of tuberculous infection in these patients. However, the usefulness of these methods in this clinical setting remains to be established.

REFERENCES 1. Gómez-Reino JJ, Carmona L, et al (BIOBADASER Group). Treatment of Rheumatoid Arthritis with Tumor Necrosis Factor inhibitors may predispose to significant increase in Tuberculosis risk. Arthritis Rheum 2003;48:2122-27.

2. Rodríguez-Valverde V, Alvaro-Gracia, Alvaro JM, et al. Actualización del consenso de la Sociedad Española de Reumatología sobre la terapia biológica en la Artritis Reumatoide.

3. British Thoracic Society standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF- α treatment. Thorax 2005;60:800-5.

4. Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, Montero D, Pascual-Gómez E et al (BIOBADASER Group). Effectiveness of Recommendations to Prevent Reactivation of Latent Tuberculosis Infection in Patients Treated with Tumor Necrosis Factor antagonists. Arthritis Rheum 2005;52:1766-72.

5. Nizam S, Emery P. Attenuated response to purified protein derivative in patients with rheumatoid arthritis. Ann Rheum Dis 2006;65:980.

6. Joven BE, Almodóvar R, Galindo M, Mateo I, Pablos JL. Does anti-tumour necrosis factor α treatment modify the tuberculin PPD response? Ann Rheum Dis 2006;65:699.

7. Ponce de León D, Acevedo-Vasquez E, Sánchez-Torres A, Cucho M, Alfaro J,Perich R et al. Attenuated response to purified protein derivative in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64:1360-61.

8. World Health Organization. Global TB data base. Global TB control report (as of 22 March 2006). www.who.int/tb.

Dear Editor,

I read with interest the article by Katz et al on the prevalence and predictors of disability in valued life activities among individuals with rheumatoid arthritis (1).

It is encouraging that patient based assessments are being explored among rheumatic diseases. Rheumatoid arthritis (RA) and osteoarthritis (OA) have received the most attention in this regard. It is thus reassuring that in this study, the Health Assessment Questionnaire (HAQ) was predictive (B 2.44 for "unable" , 6.4 for "affected" and 0.56 for "difficulty) of the overall valued activity disability.

I have some comments and queries. The study population is comprised of individuals receiving treatment from rheumatologists, and had expressed their interest in RA research. This may be a surrogate for people with positive health behaviors, compliance and better educational status. Patients that visit a rheumatologist may not reflect the general RA patient population, as they may have better access to medical care, especially for those 65 years or older (Medicare). In such recruitment, we not only compromise generalizability of the results, but also the variation in the disease spectrum. It would have been helpful to include educational status and ethnicity data, since lower educational level is known to be associated with work disability (2). Furthermore, lower socio economic status is related with disease severity, more co morbidity and higher mortality in RA (3).

The mean age of the study participants was 60 years and mainly comprised of women, the subgroups that also have a higher prevalence of osteoarthritis (OA). Can patients differentiate between limitations due to RA or their coexistent OA or other co-morbidities (obesity, cardiac or pulmonary disease, vision etc)? More than 50% of the subjects had one or more co-morbidities, as mentioned in Table 2; however the multiple regression models did not include co-morbidities as an independent variable in the models for VLA.

Knowledge about the distribution of the data and range for age, duration of disease and HAQ scores would have been helpful. Standard deviations that are larger than the mean scores, on the difficulty ratings (Table 3), may suggest the presence of outliers or lack of data. Table 3, indicates the problem with fewer observations in the difficulty ratings in the last two columns for "a lot" and "unable".

Lastly, it is not evident from the methods section about the recall period used for VLA assessments. The methods section notes a six months recall period for development of the VLA scale. However, it has since been revised as mentioned by the authors. If six month recall period was also used for this study, it may be too long a period for 60 years old patients to recall. Similarly, detail about the method used for (physician/patient) assessment of the number of swollen/painful joints would add to our knowledge, to ascertain if this is was a completely patient based assessment or included additional physician assessment.

It would be nice to see a similar study in early RA patients, so that modifiable factors (including clinical information such as lag period between disease onset to its diagnosis, time taken to start the treatment with disease modifiers, and period between onset of disease and therapeutic remission, presence of erosions, nodules, ESR/CRP, access to health care, satisfaction with treatment, compliance, education, ethnicity)which can predict potential disability in VLA, can be determined, so that we can devise ways to prevent potential disability.

Sincerely

Meenakshi Jolly, MD, MS

References

1) Katz PP, Morris A, Yelin EH. Prevalence and predictors of disability in valued life activities among individuals with rheumatoid arthritis. Ann Rheum Dis 2006;65:763-769

2) Morales-Romero J, Gonzalez-Lopez L, Celis B et al. Factors associated with permanent work disability in Mexican Patients with Rheumatoid Arthritis. A case control study. J Rheumatol 2006;33:1247-9

3) Harrison MJ, Tricker KJ, Davies L et al. The relationship between social deprivation, disease outcome measures, and response to treatment in patients with stable, long standing rheumatoid arthritis. J Rheumatol 2005;32:2330-6.

Dear Editor,

Davis et al [1] emphasize the necessity of a uniform definition of the term "disease duration" for the case of ankylosing spondylitis (AS) because different definitions have been used in the past. Besides the duration since disease onset (time of first symptoms), the duration since the time of diagnosis of AS has also sometimes been named "disease duration" [2]. We very much support the initiative for a uniform definition which would indeed ensure comparability across studies and thus facilitate future research.

The conclusion in [1] that "important components of the recommendations to better define duration of disease were found to be :

(1) time since onset of axial AS-specific symptoms (inflammatory back pain),

(2) onset of signs of spondyloarthritis, peripheral or extra-articular symptoms,

(3) onset of associated SpAs, and

(4) time since diagnosis of AS by a health-care provider" does, however, not contribute to a uniform definition.

In two recent surveys [3–5] we found that up to 48 years may lie between first symptoms of AS and the diagnosis of AS, with an average delay in diagnosis of 8.9 years and 8.8 years, respectively, in these surveys.

As an AS researcher and a rheumatologist, both with AS ourselves, we want to emphasize that using the time since diagnosis as "disease duration" does not only disregard many years of the patients' suffering from an undiagnosed but nevertheless very interfering disease. More important: This definition may lead to severe scientific errors in epidemiologic studies. If, for instance, the dependence of the extent of ankylosis on the disease duration is investigated (as in [4, 6]) and the duration between first complaints and diagnosis were neglected, an extended ankylosis found already at "disease duration" = 0 would not at all be surprising. The growth of syndesmophytes does not wait until the disease is diagnosed. If, as another example, the annual incidence of vertebral fractures and its dependence on the disease duration is investigated as in [7], a "disease duration" neglecting the disease duration before the diagnosis of AS, may likewise lead to wrong conclusions, and vertebral fractures which are in fact a result of many years with the disease may be found at negative "disease durations". These examples may illustrate why we regard a “disease duration” of AS neglecting the years before its diagnosis as being unscientific, in contrast to the authors of [1] who mention that ”the time since diagnosis of AS will aid in issues related to regulation, research, and education”.

The authors of [1] also argue that assessing disease duration by studying patient histories from medical records may lack accuracy because of missed or inappropriate diagnosis, and that this might be true for patient's recall of symptoms as well. However, replacing a possibly inaccurate value by a value which is definitely wrong by many years, makes it even worse.

We agree that the time of diagnosis should be collected in addition – besides the time of first symptoms – when data for research is collected. We regret that this is not done, for instance, in the national database of the German collaborative arthritis centres [8] where an evaluation of the delay in diagnosis of AS is therefore impossible. It is also not possible by use of this database to verify the interesting dependence of the female percentage among AS patients on the decade in which the diagnosis was made [4].

A quantity like the disease duration cannot be defined by four alternative and contradictive definitions. We would expect a clear-cut definition like, for instance: (1) In general, "disease duration" of AS is defined as the duration since onset of AS-specific symptoms (inflammatory back pain). (2) If onset of peripheral signs of spondyloarthritis precede axial symptoms, this may be used as beginning of the "disease duration". This should however be documented. (3) The onset of signs for an associated SpA without AS-specific symptoms should not be used as beginning of the “disease duration” of AS. (4) The duration since diagnosis of AS by a healthcare provider may be of interest in some connections of research but should never be called "disease duration".

Ernst Feldtkeller, PhD
Vice president of the Ankylosing Spondylitis
International Federation
Michaeliburgstr. 15, D-81671 München, Germany
Tel: 0049-89-493376
Fax: 0049-89-49003836
feldtkeller@t-online.de

Jon Erlendsson, MD, rheumatologist
President of the Ankylosing Spondylitis International Federation
Grønningen 10, DK-8700 Horsens, Denmark
jon.erlendsson@stofanet.dk

References

1. Davis JC, Dougados M, Braun J, Sieper J, van der Heijde D, and van der Linden S for the ASAS (ASsessment of Ankylosing Spondylitis) International Working Group. The Definition of Disease Duration in Ankylosing Spondylitis: Reassessing the Concept. Ann Rheum Dis 2006 Feb 7; [Epub ahead of print]

2. Spoorenberg, A. et al., A comparative study of the usefulness of the Bath Ankylosing Spondylitis Functional Index and the Dougados Functional Index in the assessment of ankylosing spondylitis. J Rheumatol 1999;26:961–965

3. Feldtkeller E. Erkrankungsalter und Diagnoseverzögerung bei Spondylarthropathien. Z Rheumatol 1999;58:21–30

4. Feldtkeller E, Bruckel J, Khan MA. Scientific contributions of ankylosing spondylitis patient advocacy groups. Curr Opin Rheumatol 12 (2000) 239-247

5. Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int 2003;23:61–66

6. Brophy S, Mackay K, Al-Saidi A, Taylor G, Calin A. The natural history of ankylosing spondylitis as defined by radiological progression. J Rheumatol. 2002;29:1236–1243

7. Feldtkeller E, Vosse D, Geusens P, van der Linden S. Prevalence and annual incidence of vertebral fractures in patients with ankylosing spondylitis. Rheumatol Int. 2006 Jan;26(3):234-239

8. Zink A, Listing J, Klindworth C, Zeidler H for the German Collaborative Arthritis Centers. The national database of the German collaborative arthritis centres: I. Structure, aims, and patients. Ann Rheum Dis 2001;60:199-206.

Dear Editor,

We read with interest the article by Dr van Eijk et al, in which they confirmed that cervical spine disorders are rare in early arthritis nowadays.[1] Their series consisted of 258 patients with a history of 2 or 5 years of chronic arthritis, and only seven cases with significant cervical spine involvement were found by 4 radiographs taken of each patient. It is easy to agree that there is no need for routine screening for these disorders in the first years of chronic arthritis. However, one should be cautious with their suggestion that cervical spine radiographs be restricted to patients with symptoms or signs indicative of the cervical involvement.

Several former papers have represented patients with clinically significant atlantoaxial subluxation (AAS) without any typical symptoms or signs of cervical origin.[2-3] Dr van Eijk et al mentioned that only three out of their seven cases with cervical involvement reported non-specific pain, and none had neurological symptoms or signs. Nevertheless, they found patients with clinically important AAS, including one very severe case (13 mm).

Specific neurological signs or symptoms cannot be the only indications to take cheap and rather safe plain radiographs aiming to diagnose potentially dangerous critical instability in the neck. The cervical involvement is caused by a chronic active inflammation and associated to a destructive disease, which was reported also by van Eijk et al.[1, 4-5] The number of patients with a refractory disease will probably be lower in the future, but in such cases, cervical spine radiographs may be indicated during the first 5 years of the disease even without cervical symptoms or signs.

All the seven abnormalities (subluxations) reported by van Eijk et al were probably diagnosed by the dynamic lateral view radiographs, however they always took also two anteroposterior (AP) views (high and low). Based on their findings and our own experiences (still unpublished data), we suggest that a routine radiological examination of the cervical spine in chronic arthritis should include lateral view radiographs in full flexion and extension, but the AP radiographs are probable needed only in advanced cases and for individual reasons.

Physicians should be aware of the possibility that significant cervical spine subluxations may develop even without symptoms or signs in cases with severe inflammation. Dynamic radiographs should be taken when such abnormalities are suspected, but it is wise to avoid unnecessary radiation.

References

1. van Eijk IC, Nielen MMJ, van Soesbergen RM, Hamburger HL, Kersten PJS, Dijkmans BAC, van Schaardenburg D. Cervical spine involvement is rare in early arthritis. Ann Rheum Dis 2006;65:973-4.

2. Neva MH, Häkkinen A, Mäkinen H, Hannonen P, Kauppi M, Sokka T. High Prevalence of Asymptomatic Cervical Spine Subluxations in Patients with Rheumatoid Arthritis Waiting for Orthopaedic Surgery. Ann Rheum Dis 2006;65:884-8.

3. Häkkinen A, Neva MH, Kauppi M, Hannonen P, Ylinen J, Mäkinen H. Jäppinen I, Sokka T: Decreased muscle strength and mobility of the neck in patients with rheumatoid arthritis and atlantoaxial disorders. Arch Phys Med Rehabil. 2005;86:1603-8.

4. Neva MH, Isomäki P, Hannonen P, Kauppi M, Krishnan E, Sokka T. Early and extensive erosiveness in peripheral joints predicts atlantoaxial subluxations in patients with rheumatoid arthritis. Arthritis Rheum 2003;48:1808-13.

5. Naranja A, Carmona I, Gavrila J, Balsa A, Belmonte MA, Tena X et al . Prevalence and associated factors of atlantoaxial luxation in a nation wide sample of rheumatoid arthritis patients. Clin Exp Rheumatol 2004;22:427-32.