4.2.5 Criteria for Fibromyalgia

The American College of Rheumatology has established criteria for ÞbromyalgiaÑ http://www.rheumatology.org/practice/clinical/ classiÞcation/index.asp (Table 4.4).

Fibromyalgia is characterized by chronic widespread pain and allodyniaÑheightened and painful response to pressure. Fibromyalgia symptoms are not restricted to pain, leading to the use of the alternative term Òcentral sensitization syndrome.Ó Other symptoms include debilitating fatigue, sleep disturbance, and joint stiffness. Some patients may also report difÞculty with swallowing, bowel and bladder abnormalities, numbness and tingling, and cognitive dysfunction.

Fibromyalgia is frequently co-morbid with psychiatric conditions such as depression and anxiety and stress-related disorders such as posttraumatic stress disorder (PTSD). However, not all people with Þbromyalgia experience all associated symptoms.

Evidence from research conducted during the last three decades has revealed abnormalities within the central nervous system (CNS) affecting brain regions that may be linked both to clinical symptoms and research phenomena. These studies show a correlation but not causation of symptoms.

Fibromyalgia is considered a controversial diagnosis, due to lacking scientiÞc consensus to its cause. Not all members of the medical community consider Þbromyalgia a disease because of the absence of objective diagnostic tests.

4.3Laboratory Results for ANA Often Drive Clinical Diagnosis

Patients are often referred to rheumatologists with vague symptoms and a positive anti-nuclear antibody (ANA) for conÞrmation of diagnosis and therapy. We try to emphasize to patients and referring physicians that SS is a clinical diagnosis that is conÞrmed by certain laboratory tests.

We will often try to clarify this discrepancy about diagnosis by providing patients with information about the currently accepted clinical diagnostic criteria.

We recognize that the clinical criteria are developed for research purposes and that antibodies may precede clinical symptoms by many years. However, it is also important to emphasize that the ANA testing is much more sensitive than speciÞc. In other words, many patients with a positive ANA may never develop any signiÞcant autoimmune disorder and that the pattern of speciÞc autoantibodies is more closely correlated with the patientÕs genetic background than with speciÞc clinical symptoms.

These diagnostic discussions (and often conflicting diagnoses among rheumatologists) must take into account that:

¥The ANA titer can differ substantially in different laboratories and even in the same laboratory when different methods are used. This is particularly a problem when ELISA methods to detect ANA are used, in comparison to tube dilution titers using immunoßuorescence assays on Hep-2 cells. Indeed, a recent

New England Journal of Medicine ÒClinical Pathologic Discussion CaseÓ had the diagnosis revolve around differences in the method used for testing for ANA [15].

◦Thus, the same laboratory may give entirely different results on the same patient sample depending on which method is used for the assay [16, 17].

¥ANA detection in SS patients differs from SLE patients, since the routine assays are set up for detection of SLE-associated antigens and the Òpositive control seraÓ used by the laboratory are derived from SLE patients with high titer antibodies to antigens such as double-stranded DNA [16, 17].

◦This may lead to a result in an SS patient such as a negative ANA but a positive SS-A antibody. Since the SS-A is located in the nucleus of all Hep-2 cells, how can we resolve this inconsistency [18Ð20]?

¥For a clinical example, we used to have a diagnosis called Òsubacute lupusÓ where the ANA was negative and the antibody to SS-A was positive. It was subsequently recognized that this paradox was the result of the high ÒacetoneÓ solubility of the SS-A antigen, which was removed during ÒoverÞxationÓ of commercially available slides [21Ð24]. The ÒcontrolÓ sera for the ANA assay is generally selected from SLE patients (often chosen for their high titer to DNA or Sm/RNP) and continued to detect positive antigens, even though the SS-A antigen had been leached out. This may lead to a misleading laboratory report that the ANA is negative when the antibody to SS-A/SS-B is positive.

◦Other problems that cause discrepancy between ANA by immunoßuorescence assay and ELISA include antigens in the nucleus (such as Þbrillary proteins or chromatin-associated antigens) which are not well solubilized.

◦Finally, certain other antigens (such as anticentromere or nucleolar proteins) may be present in speciÞc areas of the cell in high enough concentrations to be easily detected by immunoßuorescence method, but their level drops into the ÒbackgroundÓ noise level when the cell is solubilized for ELISA methods of detection.

¥Diagnosis of SS is defined by the patient’s clinical presentation and confirmed by laboratory analysis (Tables 4.2, 4.3, and 4.4) and the clinical diagnosis should be made by the pattern of their ANA.

◦The pattern of ANA (i.e., Þne speckled or centromere or nucleolar) correlates more closely with the patientÕs genotype than with their clinical presentation. Thus, ANA and their patterns/speciÞc antibodies are used to conÞrm a clinical diagnosis rather than being used as the basis of a ÒÞshing expedition.Ó

one set of criteria and should be considered an Òoverlap.Ó

4.4Disease Activity in Sjogren’s Syndrome

After a diagnosis of SS has been conÞrmed, we need to use a standardized method to determine Òwhere we have beenÓ (organ damage index) and Òwhere we are goingÓ (disease activity index). This will allow comparison of treatment and prognosis among patients at different medical centers, among different ethnic groups, and establishment of registries. The European Consortium (see Chapters 5 and 30) have provided important initial steps including disease damage and activity indexes, based in parallel to our experience in SLE data collection.

¥In each of these scales, particular manifestations are given a ÒpointÓ value, where higher point score indicates greater severity. Computer modeling by these groups has been done to help assign the Òseverity [25] pointsÓ to best reßect the clinical status as judged by an expert panel (the so-called Delphi model) (Tables 4.5 and 4.6) [26].

4.5Status of Biologic Drugs in SS Patients

Based on the dramatic success of biologic agents in rheumatoid arthritis, rheumatologists are frustrated by the relative lack of a Òmagic bulletÓ in SS and SLE with biologics. Current studies in SS using biological agents (i.e., anti-CD20 and anti-BAFF antibodies) (www.clinicaltrials. gov) are still recruiting and in progress, and several additional novel topical treatment studies are actively recruiting patients.

A number of studies using biologic agents