CONFERENCE SUMMARY Ia) vou2t + UNE 18 Fibromyalgia 2019: Myths and Realities jacob N. Ablin MD Deparment of nema Medion HT uv Sourashy Mecl Cee Tel Av alte wth Sackler Faculty of Mclcine, Telvv Unive Tel Avi ka KEY WORDS: centralized pain, chronic pain, Abromyalga, patient 26 physician relationship aro; 21: 6-28 Fritzl rome (9) lina onal of symptoms centered on chronie pain and fatigue, epito- ‘izes the concept of pain centralization within the CNS. ‘While struggling with the challenges of FMS, eheumatolo sists, as well a physicians in general, have learned a great deal regarding the nature of chronic centralized pain (nociplastic pain) [1]. They have demonstrated how much they can gain ‘when addeessng the complaints oftheir patient, rather than simply assuring them that nothing is wrong because all of the {est results are within the normal range. Major progres is being ‘ade through a collaboration between clinicians and neurosc- cntists in the effort to unravel the secrets of FMS and cen ined pain in general [2]. Nevertheless, skepticism and mistrust continue to mire the discourse between many clinicians and their FMS patients, and the lack of trust engendered by these attitudes inevitably undermines the therapeutic endeavor. “Thsarticle summarizes a presentation given in January 2018, aspart ofthe 7th taly-Lsrael 2019 Symposium of Autoimmunity and Rheumatology held at Sheba Medical Center, Tel Hashome, and the Padch Medical Center, Poriya, both in Israel This con- ference summary addresses some common misconceptions ‘regarding FMS, in an attempt to partially mitigate the negative cileets discussed. MISCONCEPTION 1: FMS IS A WOMEN’S PROBLEM, NO NEED FOR MEN TO WORRY ABOUT IT Previously, EMS was considered almost exclusively a problem for female patients, and clinicians would tend to ignore the dif {erences in the differential diagnosis of male palients present ing with widespread musculoskeletal pain [3]. This pervasive conception may have had negative consequences regarding the atitade of clinicians toward FMS. Medical issues that dispropor- tionally affect females continue tobe taken less seriously in the ‘medical community. While FMS is sil considered to be moze prevalent in females than in males (4), its curently recognized ‘that a significant proportion of FMS patients are male, This change in the female-male proportion may in part be the result of the changing criteria used for diagnosing FMS. I the 1990 American College of Rheumatology (ACR) criteria (5), muscu- Joskeletal tenderness was the main criteria for diagnosing FMS; however, the tenderness and pain criteria has subsequently ben abandoned in the newer diagnostic criteria (6) Since women generally experience more musculoskeletal tenderness than men [7], the 1990 criteria tended to underestimate the prevalence among males. On a practical note, physicians encountering a male patient presenting with widespread pain and fatigue should consider FMS in the differential diagnosis, and such patients ‘must be informed tha their condition isnot uncommon, MISCONCEPTION 2: I'S ALL IN THEIR HEAD Statements such as,"Weall in your head” are frequently offered to FMS patients by their physicians. Sometimes this message will be presented with sympathy and encouragement, for example, implying thatthe condition can somehow be overcome just by thinking in a more postive way. Other times it willbe conveyed ina much more disparaging and even accusatory tone, suchas, "Time to snap out oft” Thus, most patient fel grea frustra tion and are rehicant to establish a therapeutic relationship lronically, evolving evidence indicates that FMS realy is all inthe ead of the patient, or at east within their central nervous system, but in ways that are very different from what has previ- ‘ously been implied. As mentioned earlier, FMS is considered tobe a classic centralized pain condition, also characterized as representing a condition of central sensitization [8]; that is, a condition in which there is pain amplification in addition to reduced pain inhibition throughout the central nervous system, Altered patterns of connectivity are being studied to understand the pathogenesis of pain centralization, and such patterns may he future to enable precision medicine and to predict the response to treatment, These areas of research are leading toward the development ofa specific FMS-pain neurophysi ological signature [9] Thus, FMS really does appear to be con- nected to the central nervous system, a finding that obviously does not make the problem any less real or credulous, MISCONCEPTION 3: THESE PATIENTS ARE SIMPLY DEPRESSED; THEY NEED A GOOD PSYCHIATRIST AND AN ANTI-DEPRESSANT Infact, a significant number of FMS patient do present with co-morbid psychiatric disorders, mainly anxiety and depres-twa «yout June 2018 CONFERENCE SUMMARY sion (as do many patients presenting with other chronic il esses). Nonetheless a surprisingly significant numberof FMS patients are highly resilient despite their chronic symptoms and o not show clinically significant psychiatric symptoms [10]. Moreover, while patients experiencing major depression say have pain symptoms, they do not universally flill FMS criteria. On a practical note, the suggestion that FMS patients should regularly be managed by psyciatists appears blatantly unacceptable. Poychatrists are not trained to differentiate ‘between musculoskeletal tenderness and peripheral synovitis (as must be assessed when diagnosing FMS). Ruling out alter native causes of musculoskeletal pain, suchas an underlying seronegative spondyloarthropathy (2 common EMS lookalike) [11], would als hardly be expected fom psychiatrists. Treating FMS as co-morbdiy of an ioflammatory joint disease such as theumatid arthritis [12] would alo be extreme challeng ing, Ofcourse, there sno logical reason to send FMS patents exhibiting no psychopathology to the realm of psychiatry. Thus, ‘while psychiatric co-morbidity among FMS patients s impor tant to identify, and expert referral must be available when necessary, relegating all FMS patients tothe fed of psychiatry simply is wrong MISCONCEPTION 4: THERE 1S NO WAY To HELP THESE PATIENTS ANYWAY FMS is a chronic condition. Response to treatment is often incomplete and slow, and moreover, treating FMS patients is time-consuming and dificult. Thus, physicians may become frusteated and develop a kind of therapeutic niilism when dealing with these patients. Nonetheles, it isnot true that patients never get beter. In fact, recent evidence indicates that ‘when looking a patients previously diagnosed with FMS, many patients no longer meet FMS criteria [13]. While some ofthese findings maybe the result of n original misdiagnosis, it seems reasonable that some patients doin fact, improve to the degree of no longer meeting FMS criteria. The personal experience of physicians may be skewed because patients who realy get better ate not likely to come for follow-up, while patients who remain static or deteriorate will continue to return for treat- rent. Physicians, ike others, ae prone to use the so-called availabilty heuristic as described by Tvetsky and Kahneman [14] In this cognitive shorteu, the ease with which a person remembers relevant examples the evalbility influences the perceived frequency ofthe event, thus creating an predictable cognitive bias Based on ths bia, itis easy to understand the bhghly negative prognostic atitude toward FMS patients ‘Considerable progress has been made in formulating guide lines, including in Israel (15, fr the rational management of EMS. These guidelines emphasize the implementation of on pharmacological modes of ueatmen, suchas exercise, move ‘ment and meditative treatments, hydrotherapy, and cognitive ‘behavioral reatment (CBT) [16]. thes treatments, which are atleast moderately evidence-based, become more accessible to EMS patients, we might see more favorable outcomes. MISCONCEPTION 5: THESE PATIENTS ARE SIMPLY MALINGERING: "ANYONE CAN GO ONLINE AND MEMORIZE THE SYMPTOMS OF FMS ‘Currently the diagnosis of FMSis based entirely on clinical ri teria, ass the assessment of severity and FMS-relateddisabil- ity This unfortunate situation obviously raises dificulies and inereasesa lack of trust toward FMS patients particulary inthe medicolegal arena, The introduction of objective biomarkers ‘would certainly be very useful and a previously mentioned, a true specific neurophysiclogical FMS-pain signature would bbea tremendous step forward in this aspect, Stil, most clini- cians seem capable of identifying secondary pain issues when they emerge and distinguish FMS from malingering, However, itwould be unethical for physicians to treat all EMS patients ‘with disbelief because ofthe occasional malingerer. MISCONCEPTION 6: BUT COME ON, THIS IS ONLY FIBROMYALGIA WE ARE TALKING ABOUT, NOTHING SERIOUS. Discussions about FMS are often conducted in less than seri ‘ous tone. Students and young doctors can easily understand from role models the unstated message that FMS isnot serious ‘or may even be worthy of ridicule. This altitude is counter- productive toward patient care. It may seem unnecessary to state this approach because itis not defensiblein writin, butin actual medical prectice, ranging from doctors informal discus- sions to social media the disparaging attitude toward patients with FMS continues. Thus, we must do more to educate medi cal personnel IMSCONCEPTION 7, FlBROMYALGIA DOES NOT REALLY EXIST “his last point continues to epitomize FMS misconceptions Quit obvious if prablem doesnot exist we donot need to solve it Thus, by throwing the very existence of FMS into doubt, “bro-skepc" can avoid either treating their palin or investing efor in developing beter future solutions. This strategy appears to correspond withthe legendary Turkish admiral, who when charged withthe mission of conquering the sland of Mata, after woeflly fling to even find the iland in the Mediterranean Sea, simply reported "Malta Yok!" which translates to: therein Matta (17) Ieis someohat perplexing t argue aguinst this miscon- ception. Based on the evidence, about 2.4% ofthe Israel population i extimaed to fll FMS eters 18] and similar ‘numbers have been obtained across many ather counties. So, even if FMS does not ext, there are millions of individuals presenting with the precise constelation of symptoms, nciad- ingwidespread pain an fitigu, which we associate with EMS. ‘These individuals certainly do exist, and whoever disagrees wth the concept of FMS is welcome to come forward and sug- gest alternative or beter terminology clasifation, and patho- 47CONFERENCE SUMMARY Ia VOL 21+ UNE 209 428 genesis to deal with these patients, Until that happens, EMS is the best definition medicine ha expressed for dealing with this mense problem and we as physicians, have the responsibil ity to treat our patients with both good will and respect while doing our best to understand what FMS is. Looking the other ‘way isnot going to solve anything Correspondence De LN abn Dept of tert Medicine H, Tal uv Sourasy MesielCate Ti 4339, ae Phone: 972) 697-4000 femal acababaime gull References 1 Tee RD, Rif W, Berke A ea Chri pina tam oa eee {be US? Ghutcton of Chie Pa fr ernie Clana a ease 1CD- 1) Pen 208,100 1827 2 shia KA Clow) Nesobsopyo ronal nd rane dered pn, Neon 2016381128 4. Wolf Res K Andee Ruel Ape of Remy in he eee opti epi esi aod eos spans | Rha 185 bins 4 rior LF Wave epiemilgy orem Cir Pin Heche Rap 21 6358 5. Wolle Ssh IE, Yous, eal The Ameren Cale of Rhesmatlagy 1930 ee orth seins of Sroayagan Arte Rhee 95035 (6 Wolf Caue DE, Pacis MA, eal, 2016 Reins t he 200201 ‘rosy danas etrs Soin Atri Reon 2164613) 3192 Vectors in stealth mode Gene therapy using adeno-associated virus (RAV) vectors has shown safety and efficacy in hemophilia. However, AAV vectors have limitations hindering their efficacy in some paints, The use of lentiviral vectors (LVS) has been explored as a possible alternative; however, preclinical data reported low transduction efficacy, possibly owing to fast clearance by phagocytes. Milani et al, developed a shielded LV able to Later Defi ede partie pln manager, Ort Rat esa, 9107 {Yon MB. iba and neping dine the anihng cone of cena sens yaromes San Arts han 207366 38956 9. pee Sab, Woo CP t a Toweds a newophyslogal site fo frog Pin 37,18 0 2 10, Het AL, Fen PUL The sl of reine i hei management of rai pin. Car Pat aa ep 206, 20(6: 38 1 Abie Eke, Bernas tal reese al pedyaesismong pases wh roma meg soning ly wth apis St be Aveomest of Seniowtsiis iseriasd Sey deena {se Aris Cars sk] 2017, 69(9} 7269 12. Git AC, Goyer EK, Ea IF Lae M, Liga GO bron reais agusuorbordes eam arias Asa Dt Ba De 2421-09-48 13, Wa 3, Kas RS, Bergman MU, Wale Thre gece of peas he 1S pepsin parting» dana cagnons of Eamon ssh ‘bony ct be 12 Nato ete Sry, Plas One 206, ni@pevisras 1 Terk A, Kata , Aral 2 eae for jpg equncy and prt: Cane ey 1973 (2-207 32 15, Abi Atl, Ehreld M eta Gedling he digs snd veins! he irony syd Mag 205182125 127,751,750 16, Drama Gand DS. Ha Miia bpychoac o (pum rchonc ust pina he Deve eA 219,21 (02553 17, Renin D, Prt BA, Repo depres in eal coer: Heber ‘Singer Since snes Mey 206 1A Ae 1e A. Cae at Pelee funy tealpopelion {pupae ued uy ete be proves from eee epulton og te Landon Fbromipa Fpdemlogy Say Soveing ‘Guersoene FES) Cin sp Rac! 21230 (6 Suppl): 39-, escape phagocytosis by expressing the phagocytosis inhibitor CD47 on its surface, With intravenous administration in monkeys, the LVs showed high transduction efficacy without signs of toxicity, Thus, mediated gene therapy might be an cflectve strategy for treating hemophila. ‘Se Trans! Med 2018: 11: eav7305 tan ae Gitrobacter rodentium alters the mouse colonic miRNome Gitrobacter rodentium is @ murine pathogen that causes transmissible colonic hyperplasia and colts with a pathogenic, mechanism similar to foodborne enterahaemarthagic Escherichia colin humans. Mechanisms underying intestinal responses to C. rodentium infection not completely under stood, Wen et a. identified 24 colonic microRNAs (miRNAs) as significantly deregulated in response to C. rodentium, including miR-73, 17, 18a, -20a, 20, 82a, 1063, 192, 200a, and -2137. Most of these miRNAs belong to the oncogenic ImiR-17-90 clusters. Pathways involved in cell cycle, cancers, and Immune responses were enriched among the predicted targets of these miRNAs. The authors further demonstrated that an apoptosis facilitator, Bim, isa candidate gene target of miRNA-mediated host response to the infection. These findings suggest that host miRNAs patipate in C. rodentium pathogenesis and may epresent novel treatment targets. Genes & Immunity 2018, 20207 tan ae