The most relevant finding of the present study was the remarkable improvement achieved for all outcome measures after one year of uninterrupted GFD in 7 CD females previously categorized as severe IBS/FMS patients recruited through case-finding among IBS and FMS patients.
Curiously, the clinical presentation of these “IBS/FMS CD-associated” patients exhibited a repetitive chronological sequence, usually starting as gastrointestinal relapsing disorders, frequently misclassified as IBS, when the patients were in their 20s and 30s, becoming multisystem “FMS-like” complaints around their mid-40s. Notably, about 30% of these patients mentioned having other first-degree relatives diagnosed with CD. In addition, they scored very poorly in TPs and HR-QoL tests, and as this negative clinical picture would suggest, these patients reported not only frequent use of healthcare services and multiple drug prescriptions, but also low rates of medication adherence due to drug intolerance, lack of effectiveness, or drug-related adverse effects. Finally, an excess of associated diseases and a high prevalence of circulating autoantibodies were documented.
After 1-year of sustained GFD, a very significant decrease (ranging from 51 to 60%) in TPs, FIQ, HAQ and VAS mean scores, and a positive change of 48% and 60% in the SF-36 physical and mental scores, respectively, were observed. For example, the FIQ mean score decreased from more than 60 to less than 39 (i.e., from “severe” to “mild” FMS); the mean HAQ score category changed from “much difficulty” to “able to do with some difficulty”; the VAS for digestive symptoms changed from “moderate/severe” to “slight/moderate” intensity; the VAS for the amount of pain changed from “very bad” to “not too bad”, and a similar result was obtained for the amount of fatigue patients felt. Alongside this clinical improvement, a significant decrease of 55% in both the number and doses of prescribed drugs was reported, and interestingly, the unpleasant manifestations of some associated diseases, such as chronic urticaria, improved significantly. On the other hand, the basal tTG-2, TPO and AMA serum levels steadily dropped to normal values in all patients.
CD is a multisystem autoimmune disorder related to a permanent intolerance of gluten (a protein found in bread, pasta, cookies, pizza crust and many other foods containing wheat, barley or rye) that affects 1-2% of the population (mainly females) worldwide, with subjects generally being carriers of one of the two HLA-II genotypes, DQ2 and DQ8. In these subjects, gliadin peptides trigger an aberrant immune response, resulting in the production of tTG autoantibodies, and an immune-mediated chronic inflammation of the small bowel mucosa, characterized by villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia. Clinical manifestations of CD may appear at any age, with gastrointestinal and/or extra-intestinal systemic symptoms, although some diagnoses can be made in asymptomatic individuals. Notably, a gluten-free diet (GFD) results in complete clinical remission and full recovery of the intestine in the vast majority of CD patients [28, 29].
On the other hand, FMS is a complex chronic pain syndrome affecting around 2% of the population (mainly females) worldwide, characterized by widespread soft-tissue pain, generalized tender points, abnormal fatigue, non-restorative sleep, and a variety of additional symptoms. Its pathogenesis remains elusive, and no analytical test or imaging techniques for objective diagnosis are currently available. Thus, an exclusion diagnosis must be used when other typified diseases are ruled out after an appropriate evaluation study in patients fulfilling the American College of Rheumatology (ACR) 1990 criteria for FMS . Another troubling aspect of FMS is the lack of effective therapy for controlling its symptoms, which makes it a major source of personal, family and social disturbances, and leads to heavy use of health care services, increased work absenteeism, disability and early retirement [30–32].
The striking results of the present trial suggest that a triggering gluten-related autoimmune inflammatory process within the gastrointestinal tract may end up contributing to the onset or increasing the well-documented central nervous system sensitivity responsible for FMS disorder in some CD- or gluten-sensitive individuals . This hypothesis appears to be consistent with the increased prevalence of FMS described in women with different chronic inflammatory processes within the gastrointestinal tract [31, 32], and with the fact that our patients reported a long-term history of gastrointestinal complaints preceding the onset of generalized FMS symptoms by decades. Specifically, the comorbid triad of IBS, chronic fatigue and musculoskeletal pain has been considered striking, and other authors have suggested that it may point to an underlying common food hypersensitivity-related mechanism .
ANAs were positive in three cases, but none fulfilled the ACR 1982 criteria required for a diagnosis of Systemic Lupus Erythematosus . High serum levels of anti-TPO were found in two cases with minor and transitory thyroid function test result alterations, and AMA antibodies were positive in one case presenting mild elevations of serum liver enzymes without clinical manifestations of liver disease.
Autoantibodies are a characteristic feature of CD, and it is thought that they contribute to the extra-intestinal organ involvement by attacking multiple body cells, finally causing inflammatory damage through an antigen-antibody interaction at the vascular level. In fact, 75% of CD patients have anti-TG2/TG3/TG6 circulating antibodies in blood vessels [33, 34], and although anti-tTG2 antibodies are primarily deposited in the intestine, they have also been found in a diversity of other tissues such as skin, oral mucosa, muscle, liver, cerebellum, lymph nodes, etc., whereas anti-gliadin antibodies have been reported to bind to Purkinje cells and dorsal root ganglion neurons [35, 36].
The findings of the present trial may have some biases arising from the small number of patients involved and from the lack of reliable biomarkers for IBS and FMS diagnosis/follow-up (compulsorily based on questionnaires, which are inevitably subjective). Our results are nevertheless promising, because apart from providing new research perspectives on IBS and FMS, a relatively poorly understood area of scientific knowledge, the detection of misdiagnosed CD-related IBS/FMS cases would lead to the implementation of a GFD, a simple therapeutic action that could kill two birds with one stone by simultaneously improving gastrointestinal and extra-intestinal symptoms. Furthermore, in the long term, it could prevent further CD-associated complications in patients and undiagnosed relatives at risk of developing overt CD.