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Low Sensitivity of Anti-a-Fodrin Antibodies in Patients with Primary Sjögren's Syndrome

To the Editor:

We read with interest the article by Witte, et al¹ relating to the prevalence of anti-a-fodrin antibodies in patients with primary Sjögren's syndrome (pSS). They found greater diagnostic sensitivity in patients classified according to the San Diego criteria² (88% IgA, 64% IgG) than in those classified on the basis of the criteria proposed by the European Community Study Group³ (63% IgA, 49% IgG). According to Witte, et al, application of the European classification criteria, which do not necessarily require a biopsy of the minor salivary glands, involves the risks of including patients with sicca syndrome but not SS. Conversely, using the more restrictive US criteria, which require a positive histological examination, the classification of pSS would be more accurate, and in this case, the overall positivity of the anti-a-fodrin antibodies (IgA and IgG) would be in excess of 90%.

We studied 174 patients with pSS to evaluate the sensitivity of the test for anti-a-fodrin antibodies, 141 patients with other connective tissue disorders or viral infections, and 40 healthy subjects to evaluate its specificity. Of 174 patients with pSS, the disorder was classified according to the European criteria in a subgroup of 123 patients, and according to the US criteria in a subgroup of 51 patients. Anti-a-fodrin antibodies of class IgA and IgG were studied in parallel with 2 solid-phase immunoenzymatic methods, with kits from Aesku.lab Diagnostika (Wandelsheim, Germany) and Orgentec Diagnostika (Mainz, Germany). Both tests were performed according to the manufacturer's instructions, using the cutoffs recommended by each.

The overall sensitivity of the test for antibodies of class IgA and IgG was 22.9% and 15.5%, respectively, for the Aesku.lab method and 19.8% and 12.7% for the Orgentec method. In the subgroup of 51 patients whose diagnosis included a positive biopsy among the classification criteria, the sensitivity for IgA and IgG was 17.6% and 9.8% for Aesku.lab, and 13.7% and 11.8% for Orgentec. The specificity was 91.5% for the Aesku.lab method and 90% for the Orgentec method. The global agreement (positives/negatives) between the 2 methods was 73% for IgA and 72% for IgG, but much lower (20% IgA, 3% IgG) for positive cases only (Table 1). It is noteworthy that, while only 7% of patients were recognized as IgA positive and 1% IgG positive by both methods, positive cases by either of the 2 methods were 34% for IgA and 29% for IgG, showing that the 2 tests identified 2 different anti-a-fodrin positive pSS populations. The percentage of positivity for other antibodies was as follows: antinuclear antibodies 97.1% (by indirect immunofluorescence; Inova, San Diego, CA, USA); anti-Ro, 86.8%; anti-La, 43.8% (ELISA; Diasorin, Saluggia, Italy). None of the 3 antibodies proved to correlate with anti-a-fodrin IgA or IgG.

Table 1. Percentage distribution of IgG anti-a-fodrin results achieved by the 2 kits employed, in 174 patients with Sjögren's syndrome.

Thus, our findings do not confirm those obtained by Witte, et al. On the contrary, the results in our group of patients with pSS confirmed by biopsy were actually worse in terms of sensitivity. There is no clear explanation for this great discrepancy. However, our results confirm those obtained by other researchers^4,5, showing that in general the good specificity value of anti-a-fodrin antibodies is not matched by acceptable sensitivity. This finding may be due to low nosographic sensitivity (as in the case of the anti-Sm antibodies in systemic lupus erythematosus or anti-synthetases in polymyositis), or to the fact that the current antigen formulations do not have all the relevant epitopes (low analytical sensitivity). In view of the low agreement between the 2 methods used, the second hypothesis is more probable, and it will be necessary to await the introduction of second-generation methods in order to evaluate the efficacy of this new antibody measure in the laboratory diagnosis of SS.

NICOLA BIZZARO, MD, Laboratorio di Patologia Clinica, Ospedale Civile, S. Donà di Piave (VE); DANILO VILLALTA, MD, Servizio di Immunologia e Microbiologia, Azienda Ospedaliera "S. Maria degli Angeli," Pordenone; ELIO TONUTTI, MD, Istituto di Chimica Clinica, Azienda Ospedaliera "S. Maria della Misericordia," Udine, Italy. E-mail: nbizzaro@dacos.it

REFERENCES

1. Witte T, Matthias T, Oppermann M, et al. Prevalence of antibodies against a-fodrin in Sjögren's syndrome: comparison of 2 sets of classification criteria. J Rheumatol 2003;30:2157-9.

2. Fox RI, Robinson CA, Curd JG, Kozin F, Howell FV. Sjögren's syndrome. Proposed criteria for classification. Arthritis Rheum 1986;29:577-85.

3. Vitali C, Bombardieri S, Moutsopoulos HM, et al. Assessment of the European classification criteria for Sjögren's syndrome in a series of clinically defined cases: results of a prospective multicentre study. The European Study Group on Diagnostic Criteria for Sjögren's Syndrome. Ann Rheum Dis 1996;55:116-21.

4. Sibilia J, Goetz J, Gottenberg JE, et al. Anti-fodrin antibodies detected by ELISA are not useful diagnostic markers for primary Sjögren's syndrome [abstract]. Arthritis Rheum 2002;46 Suppl:S362.

5. Nordmark G, Rorsman F, Rönnblom L, et al. Autoantibodies to a-fodrin in primary Sjögren's syndrome and SLE detected by an in vitro transcription and translation assay. Clin Exp Rheumatol 2003;21:49-56.

Dr. Witte, et al reply

To the Editor:

In order to determine the role of antibodies against a-fodrin in Sjögren's syndrome (SS), we deliberately collaborated with a number of groups. In those studies with carefully selected, untreated patients, the prevalence of antibodies against a-fodrin in SS was 77% in patients from Freiburg, 55% in patients from Munich, and 72% in our own patients¹. In another independent blinded study, the prevalence was 70% in patients from Lille, France². However, a few other groups, including Dr. Bizzaro and colleagues, have reported a lower prevalence of antibodies against a-fodrin. In many cases, the differences can be explained by a less than optimal selection of patients, in whom sicca syndrome had not been clearly differentiated from SS.

In the study from Bizzaro, et al, patients apparently were carefully selected, but still there remain 2 problems: (1) In the studies of our colleagues from Israel, the concentration of antibodies against a-fodrin correlated with the lymphocytic infiltration in the salivary glands and appears to reflect disease activity. According to our own observations, the concentration of antibodies against a-fodrin normalizes 4–8 weeks after treatment with antimalarials, low dose corticosteroids, or immunosuppressives has been started. Low prevalences of antibodies against a-fodrin have therefore been observed by colleagues who tend to treat SS with these drugs. Optimally, the prevalence of antibodies against a-fodrin has to be studied in untreated patients, as we have done. (2) At the time, when we used Aesku.lab ELISA kits for our studies, the plates were used very soon after production. According to information from Aesku.lab, Dr. Bizzaro tested the Aesku.lab kit as one of the first after larger production of ELISA plates had started, and the plates were stored for a longer period. However, it turned out that a-fodrin was an extremely unstable protein and that several epitopes tended to degrade even when the protein was coupled to the plates. Therefore, although the controls directed against epitopes that were not affected looked fine, many sera that had been positive before lost activity. That also explains the low sensitivity reported by Sibilia, et al³, who tested the kit at the same time as Bizzaro. The problem with the stability of a-fodrin had been fixed shortly after Bizzaro had tested the assay, and we have not had problems even after introducing the test into our routine laboratory diagnostics.

Even though we think that the results described by Bizzaro, et al will be similar to our own studies, when the test is repeated on untreated patients only, their comments exemplify problems in diagnostic procedures for SS. If classification criteria are used uniformly, the prevalence of diagnostic markers should be comparable in all studies. Therefore, as we wanted to assert in our study, the true association of markers with Sjögren's syndrome will only be determined when genetic risk markers have been identified.

TORSTEN WITTE, MD, Abteilung Klinische Immunologie, Medizinische Hochschule Hannover; TORSTEN MATTHIAS, Managing Director, Aesku.lab Diagnostika, Wandelsheim, Germany; MARTINA OPPERMANN; KLAUS HELMKE, MD, Professor of Internal Medicine, IV Med. Abteilung Rheumatologie und Klin. Immunologie, Krankenhaus Bogenhausen, München-Bogenhausen; HANS H. PETER, MD, Professor of Internal Medicine, Department of Rheumatology and Immunology, Albert-Ludwigs-Universität; REINHOLD E. SCHMIDT, MD, Professor of Internal Medicine, Abteilung Klinische Immunologie, Medizinische Hochschule, Hannover, Germany. E-mail: witte.torsten@mh.hannover.de

REFERENCES

1. Witte T, Matthias T, Oppermann M, et al. Prevalence of antibodies against alpha-fodrin in Sjogren's syndrome: comparison of 2 sets of classification criteria. J Rheumatol 2003;30:2157-9.

2. de Seze J, Dubucquoi S, Fauchais AL, et al. Alpha-fodrin autoantibodies in the differential diagnosis of MS and Sjogren syndrome. Neurology 2003;61:268-9.

3. Sibilia J, Goetz J, Gottenberg JE, et al. Anti-fodrin antibodies detected by ELISA are not useful diagnostic markers for primary Sjogren syndrome [abstract]. Arthritis Rheum 2002;46 Suppl:S362.

Economic Cost and Epidemiological Characteristics of Fibromyalgia

To the Editors:

Your correspondents, Drs. Dobkin and Bernatsky, have misquoted us¹. We have never argued that "the use of the diagnostic label contributes to the spread of misinformation and perpetuation of an epidemic."

Our main message is and has always been to point out that the fibromyalgia label has become clinically meaningless, thus failing the test of medical utility for the subject in persistent pain^2-4.

In contrast to Dr. Ehrlich⁵, we have provided another (neuroscientifically based) way of processing the clinical problem of widespread musculoskeletal pain and tenderness, the existence of which we have never denied³.

Surely it is now time to end the debate about the name and focus upon a better understanding of these clinical phenomena.

JOHN QUINTNER, MB, MRCP, FFPMANZCA; MILTON COHEN, MD, FRACP, FFPMANZCA, Mt. Claremont, Australia 6010.

E-mail:quintner@aceonline.com.au

REFERENCES

1. Dobkin PL, Bernatsky S. Economic cost and epidemiological characteristics of fibromyalgia [reply]. J Rheumatol 2004; 31:195.

2. Cohen ML, Quintner JL. Fibromyalgia syndrome: a problem of tautology. Lancet 1993; 342:906–9.

3. Quintner JL, Cohen ML. Fibromyalgia falls foul of a fallacy. Lancet 1999; 353:1092–4.

4. Quintner J, Buchanan D, Cohen M, Taylor A. Signification and pain: a semiotic reading of fibromyalgia. Theor Med Bioeth 2003; 24:345–54.

5. Ehrlich GE. Economic cost and epidemiological characteristics of fibromyalgia [letter]. J Rheumatol 2004; 31:195.

Dr. Dobkin replies

To the Editor:

I wish to apologize to your correspondents, Drs. Quintner and Cohen, if I have inadvertently misquoted them in my correspondence with the Editor.

PATRICIA L. DOBKIN, PhD, Associate Professor, Department of Medicine, McGill University Health Centre, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada.

The Treatment of Enthesitis in Psoriatic Arthritis

To the Editor:

We read with interest van Denderen, et al's¹ recent study on the efficacy of mesalazine in the treatment of ankylosing spondylitis (AS). We performed a similar study in patients with psoriatic arthritis (PsA), which also belongs to the seronegative spondyloarthropathy (SpA) group. We used sulfasalazine (SSZ), a treatment for inflammatory bowel disease and rheumatoid arthritis. We were particularly interested in enthesitis, which is a cardinal feature of AS as well.

Although the majority of patients with PsA run a benign course, in 20% a chronic progressive deforming arthritis may develop. A characteristic finding is enthesopathy, which is said to be common². Enthesopathy may occur in the absence of other joint symptoms and is poorly recognized in previous studies on PsA³. It has been estimated to have a prevalence as high as 38%⁴. SSZ is often used in PsA and has been found to be safe, well tolerated, and effective^5,6.

We assessed the effect of SSZ in the treatment of enthesitis in patients with PsA, using the Newcastle Enthesis Index (EI)⁷, Disease Activity Score 28 (DAS-28), and Health Assessment Questionnaire (HAQ), with improvement in these 3 scores as the primary outcome measure.

We performed an open study; patients invited to take part were older than 16 years, had PsA and enthesitis as defined by EI with a score ≥ 1, and had psoriatic skin lesions or nail changes. Standard dosages of SSZ were used⁸. Exclusions were oral steroids or other concurrent disease modifying antirheumatic drug. Patients were assessed within 4 weeks of commencing SSZ treatment, and at 3 and 6 months after treatment began. At each visit the EI, DAS-28, and HAQ were assessed.

Over a period of 22 months 26 consecutive patients with PsA and enthesitis were identified. Four declined SSZ treatment after discussion regarding the use and monitoring of the drug. Of the remaining 22, two were not able to be assessed within 4 weeks of starting treatment due to difficulties in arranging an appointment. Twenty began SSZ and had a baseline assessment. One continued SSZ but did not respond to contact for further participation in the study. Two patients could not attend for monitoring due to work reasons; the drug was therefore discontinued by the patient (both men). Nine discontinued treatment (7 women, 2 men). Reasons for discontinuation included gastrointestinal side effects (n = 4), headaches (n = 1), dyspepsia + rash (n = 1), and other side effects (n = 1). Ten patients completed 6 months of SSZ (6 women, 4 men).

Of the 20 patients assessed at baseline there were 13 women and 7 men. Their mean age was 49 years and the erythrocyte sedimentation rate (ESR) at baseline was 10.2 mm/h (range 1–48). Mean HAQ was 1.656 (range 0.125–3), mean DAS-28 4.146 (range 1.22–6.29), and EI 21.35 (range 1–50) (maximum EI score = 90). Results for the 10 subjects who completed the study period of 6 months are shown in Table 1.

Table 1. Outcomes of study completers. Values are mean (range).

Although overall trends of improvement were observed in all assessments, these results did not reach statistical significance. Similar trends were found in patients' own assessment of pain and physicians' global assessment. There were no significant differences in baseline characteristics between the responders and nonresponders.

We also found no significant improvement in any outcome measure used; however, our numbers are small. We had a high dropout rate due to inconvenience of taking the drug and subsequent monitoring, and also a high incidence of side effects: 7/24 (29%) of our study patients withdrew because of these, compared to 8/20 (40%) in the van Denderen, et al group¹. However, the HAQ scores show a level of disability and DAS-28 scores a level of disease activity that suggest this group of patients should receive treatment. ESR does not reflect disease in this population.

We found results using aminosalicylates in this seronegative arthritis group were similar to those of van Denderen, et al in AS.

A more effective and better tolerated treatment for psoriatic enthesitis is needed.

NAMITA KUMAR, MMEd, MRCP, Research Registrar Rheumatology; LESLEY J. KAY, MA, MSc, MRCP, Consultant Rheumatologist; DAVID J. WALKER, MD, MRCP, Consultant Rheumatologist, Department of Rheumatology, Musculoskeletal Unit, Freeman Hospital, High Heaton, Newcastle-upon-Tyne, NE7 7DN, UK.

REFERENCES

1. van Denderen JC, van der Horst-Bruinsma IE, Bezemer PD, Dijkmans BAC. Efficacy and safety of mesalazine (salofalkreg) in an open study of 20 patients with ankylosing spondylitis. J Rheumatol 2003;30:1558-60.

2. Gladman DD. Psoriatic arthritis. In: Maddison PJ, Isenberg DA, Woo P, Glass DN, editors. Oxford textbook of rheumatology. Oxford: Oxford University Press; 1998.

3. Salvarani C, Cantini F, Olivieri I, et al. Isolated peripheral enthesitis and/or dactylitis: a subset of psoriatic arthritis. J Rheumatol 1997;24:1106-10.

4. Kane D, Stafford L, Bresnihan B, FitzGerald O. A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience. Rheumatology Oxford 2003;42:1460-8.

5. Dougados M, van der Linden S, Leirisalo-Repo M, et al. Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind placebo-controlled study. Arthritis Rheum 1995;38:618-27.

6. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulphasalazine and placebo for the treatment of axial and peripheral articular manifestations of the sero-negative spondylarthropathies: a Department of Veterans Co-operative Study. Arthritis Rheum 1999;42:2325-9.

7. Mander M, Simpson JM, McLellan A, Walker D, Goodacre JA, Dick WC. Studies with an enthesis index as a method of clinical assessment in ankylosing spondylitis. Ann Rheum Dis 1987;46:197-202.

8. National Guidelines for the Monitoring of Second Line Drugs. British Society for Rheumatology. July 2000. Internet [cited May 19, 2004]. Available from: http://www.msecportal.org/portal/editorial/PublicPages/bsr/536883013/3.doc

Dr. van der Horst-Bruinsma replies

To the Editor:

On behalf of my co-authors I would like to thank Dr. Kumar, et al for referring to our article and for their execution of a more or less comparable study. However, there are some main differences between their study and ours that I would like to discuss.

First of all, the patients included in our study were diagnosed as ankylosing spondylitis (AS) according to the modified New York criteria and had no other forms of spondyloarthropathy (SpA), such as psoriatic arthritis. Moreover, our focus was not directed to the decrease of enthesitis or arthritis, but to other outcome measures such as the Bath Ankylosing Spondylitis Disease, Functional, and Metrology indexes.

The only corresponding outcome variable shared by both studies is the erythrocyte sedimentation rate (ESR), which decreased in our study, but remained the same in the 10 patients that completed the 6-month followup period.

Another discrepancy is the choice of the drug: mesalazine (Salofalk^®) used in our study is not the same compound as sulfasalazine (SSZ), which is supposed to cause more gastrointestinal side effects than other sulfa preparations. Mesalazine is not commonly used in AS or SpA, whereas for years SSZ has been considered an effective therapy in rheumatoid arthritis, psoriatic arthritis, AS, and SpA^5,6.

Studies on SpA show an efficacy of SSZ in improvement of the ESR and peripheral arthritis, but not in spinal mobility, morning stiffness, or other disease activity scores. Table 1 of Kumar, et al shows a small, but insignificant, improvement in the Disease Activity Score. This might be due to an improvement of the joint score, since the ESR remained constant. It would be interesting to give the swollen and tender joint count as a separate outcome measure.

The main observation in their study, that the enthesitis index does not improve with SSZ, is not surprising, taking into account the therapy-resistant course of enthesitis. Treatment with tumor necrosis factor-blocking agents would probably be more effective.

The high number of side effects of SSZ is unexpected. This might be due to the dosage, slow increase in the starting dose, and the sort of tablets used (enteric-coated or not). It would be interesting to learn of these aspects, as in many studies with SpA, a relatively high dose of 3 g daily was used.

The last point I would like to bring up is the high number of noncompleters (50%). Perhaps the results might change if an intention-to-treat analysis is performed.

In conclusion, I think it is interesting to study whether enthesitis can be influenced by DMARD therapy. However, the disappointing results might be due to the therapy-resistant outcome measure that was chosen, namely enthesitis. Perhaps an intention-to-treat analysis would result in more positive results.

IRENE E. van der HORST-BRUINSMA, MD, PhD, Rheumatologist, VU University Medical Centre, Amsterdam, The Netherlands.