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Abstract

Marine invertebrates are rich sources of bioactive compounds and their biotechnological potential attracts scientific and economic interest worldwide. Although sponges are the foremost providers of marine bioactive compounds, cnidarians are also being studied with promising results. This diverse group of marine invertebrates includes over 11,000 species, 7500 of them belonging to the class Anthozoa. We present an overview of some of the most promising marine bioactive compounds from a therapeutic point of view isolated from cnidarians in the first decade of the 21st century. Anthozoan orders Alcyonacea and Gorgonacea exhibit by far the highest number of species yielding promising compounds. Antitumor activity has been the major area of interest in the screening of cnidarian compounds, the most promising ones being terpenoids (monoterpenoids, diterpenoids, sesquiterpenoids). We also discuss the future of bioprospecting for new marine bioactive compounds produced by cnidarians.

1. Introduction

In terms of biodiversity, marine environments are among the richest and most complex ecosystems. Harsh chemical and physical conditions in the environment have been important drivers for the production of a variety of molecules with unique structural features. These marine molecules exhibit various types of biological activities [1], with compounds of high economic interest having potential applications in the pharmaceutical and medical sectors. Although nearly 20,000 compounds have been discovered since the field of marine bioactive compound biochemistry began in the mid-1960s, only a very limited number have seen industrial application. It has been clear since marine bioprospecting began that the world’s oceans and their diverse biota represent a significant resource, perhaps the greatest resource on Earth, for the discovery of new bioactive compounds. Early National Cancer Institute (NCI) programs in the USA demonstrated that marine invertebrates were a superb source of potential lead molecules. The decisive boost to this new age of bioprospecting was provided by the NCI when it was found that bioassays with marine organism extracts were far more likely to yield anticancer drugs than terrestrial sources []. In this way, it is not surprising that over the past 40 years major advances in the discovery of marine drugs have been recorded in clinical trials for cancer []. Apart from anticancer activity, these compounds have proven to be an abundant source of pharmacologically active agents for the production of therapeutic entities [] against AIDS, inflammatory conditions and microbial diseases.

Marine bioactive compounds display varied potential applications, namely as molecular tools, in cosmetics, as fine chemicals, as nutraceuticals and in agrochemical industries [5]. Although only a few marine-derived products are currently on the market (e.g., Prialt^® and Yondelis^®), several new compounds are now in the clinical pipeline and several more are in clinical development. The few approvals so far for the commercialization of drugs from the sea have not been due to a lack of discovery of novel marine bioactive compounds, but because of the complexity of issues raised upon the development of these products []. Faulkner [6–], Blunt et al. [–], and Mayer [–] have provided extensive reviews on the total number of marine natural products (MNPs) discovered over the last 25 years, the most promising ones being produced by marine invertebrates. Sponges (phylum Porifera) have long been recognized as the most interesting group of marine invertebrates for the discovery of new drugs [5,]. However, with growing bioprospecting efforts and the screening of previously unexplored marine habitats, the biotechnological potential of other groups of marine invertebrates has also started to attract the attention of researchers. The ability of cnidarians (such as jellyfish, sea anemones and corals) to produce powerful toxins and venoms [] has been well documented. However, further research has demonstrated that MNPs produced by cnidarians are more than toxins and venoms. The phylum Cnidaria is a large, diverse and ecologically important group of marine invertebrates that includes over 11,000 extant species [42]. Over 3000 MNPs have been described from this phylum alone, mostly in the last decade.

In this work, we present an overview of the most promising marine bioactive compounds isolated from cnidarians in the first decade of the 21st century, which may have applications in the therapy of human diseases. The present study also discusses future perspectives for the bioprospecting of new MNPs produced by this speciose group of marine invertebrates.

2. Methodology

The most relevant peer reviewed literature published during the first decade of the 21st century covering MNPs was surveyed for the present work [–]. During this period alone, over 2000 molecules from cnidarians were described. In order to focus our study and address only those compounds displaying a high potential for industrial applications, we have decided to use as guidelines the values of IC₅₀ (half maximal inhibitory concentration). IC₅₀ is a quantitative measure which indicates how much of a particular substance (inhibitor) is needed to inhibit a given biological process or component of a process by half. It is important to highlight that the NCI has renamed the IC₅₀ to GI₅₀ [43] in order to emphasize the correction for cell count at time zero in cancer cells; in this way, some results on this quantitative measure are now also presented under these directives. Additionally, the ED₅₀ (the median dose that produces the desired effect of a drug in half the test population) was also used to identify promising marine bioactive compounds produced by cnidarians. Only the compounds displaying an IC₅₀ ≤ 10.0 μg/mL or μM (except where stated otherwise) and ED₅₀ ≤ 4.0 μg/mL were considered for the present study, as these values are commonly used in the surveyed literature to ascertain relevant bioactivity (e.g., [,]). In the few cases were neither IC₅₀ nor ED₅₀ values were described for a MNP in a manuscript, that compound was selected to be part of the present survey only if either the authors of that manuscript, or those citing that manuscript, clearly stated that the results recorded were highly promising for industrial applications. All species producing the compounds selected for the present work were grouped into classes and orders of phylum Cnidaria (Table 1) (according to the classification proposed in the World Register of Marine Species (WoRMS)) [46].

Table 1

Classes and orders in the phylum Cnidaria followed in this paper.

This approach allowed us to identify which taxonomic groups of cnidarians screened so far display the highest potential to yield new drugs or pharmacological products derived from marine bioactive compounds. Nonetheless, it is important to highlight that cnidarian species identification is a challenging task and it is possible that some of the species (or even genera) referred to in the scientific literature may not be correct [47]. In this way, it is of paramount importance that in future works the authors addressing marine bioactive compounds produced by cnidarians provide a detailed description on how target species have been identified.

3. Class Anthozoa

Class Anthozoa currently includes 10 orders and over 7500 valid species (about 2/3 of all known cnidarian species) (Table 1). Within the Anthozoa, the order Alcyonacea (soft corals) and Gorgonacea (sea fans) are the ones which have contributed with the highest number of promising bioactive marine compounds, although other orders, such as Actiniaria (sea anemones) and Scleractinia (hard corals), have also yielded relevant compounds [–].

3.1. Order Alcyonacea (Soft Corals)

Soft corals are generally brightly colored and rich in nutritionally important substances. However, the incidence of predation in the majority of these organisms is low due to the toxic compounds they produce to deter predators [52]. Several biosynthetic studies have been carried out on the metabolites of soft corals [53] and some of those compounds have already shown to have great potential for the development of new pharmaceuticals and antifoulants. Table 2 summarizes the most promising compounds from order Alcyonacea (class Anthozoa) described in the present review.

Table 2

Most promising compounds studied in the last decade from cnidarian species in order Alcyonacea (soft corals), class Anthozoa.

AUS: Australia; DE: Germany; ISR: Israel; JPN: Japan; PHL: Philippines; RSC: Republic of Seychelles; RUS: Russia; TAIW: Taiwan; VN: Vietnam.

Soft corals are rich sources of secondary metabolites such as diterpenes, sesquiterpenes, furanoditerpenes, terpenoids, capnellenes and steroids (e.g., Lobophytum, Sinularia (Figure 1A), Sarcophyton [86] (Figure 1C), Capnella [], Dendronephthya []), that have shown to display HIV-inhibitory [], cytotoxic [88,], anti-inflammatory [90,91], anticancer [92,] and antimicrobial activity [], as well as cardiac and vascular responses []. Soft corals of the family Nephtheidae are known for their content of sesquiterpenes and particularly capnellenes []. Some sesquiterpenes isolated from Capnella imbricate [,96–98] showed anti-inflammatory activity and a dihydroxycapnellene (capnell-9(12)-ene-8β,10α-diol) from Dendronephthya rubeola demonstrated a good antiproliferative activity against murine fibroblasts cell line (L-929, GI₅₀ 6.8 μM/L) and a good cytotoxicity against cancer cell lines implicated in human leukemia (K-562, IC₅₀ 0.7 μM) and human cervix carcinoma (HeLa, IC₅₀ 7.6 μM) []. Capnell-9(12)-ene-8β,10α-diol strongly inhibits the interaction of the oncogenic transcription factor Myc with its partner protein Max [,], making it a therapeutically interesting compound in oncology []. Nephthea chabroli also produces a nor-sisquiterpene compound, chabranol, which displays moderate cytotoxicity against P-388 (mouse lymphocytic leukemia cells) with an ED₅₀ 1.81 μg/mL []. Nephthea erecta produces two proteins in mediated inflammatory responses, the oxygenated ergostanoids 1 and 3. These compounds at a concentration of 10 μM significantly reduced the levels of the iNOS (inducible nitric oxide synthase) (45.8 ± 9.9 and 33.6 ± 20.6%, respectively) and COX-2 (cyclooxygenase-2) protein (68.1 ± 2.3 and 10.3 ± 6.2%, respectively), when compared with the control cells stimulated with lipopolysaccharides (LPS) [].

Some cnidarians addressed in this review (all images by Ricardo Calado). (A) Sinularia sp.; (B) Xenia sp.; (C) Sarcophyton sp.; (D) Briareum sp.

Species in the genus Xenia (family Xeniidae) (Figure 1B) are a rich source of diterpenoids. Xeniolides I, isolated from Xenia novaebrittanniae demonstrated antibacterial activity at a concentration of 1.25 mg/mL in Escherichia coli ATCC and Bacillus subtilis [85]. Blumiolide C, a diterpenoid from the Xenia blumi (presently accepted as Xenia plicata), exhibited potent cytotoxicity against mouse lymphocytic leukemia (P-388, ED₅₀ 0.2 μg/mL) and human colon adenocarcinoma (HT-29, ED₅₀ 0.5 μg/mL) cells [].

Polyoxygenated cembranoids, crassocolides H–M from Sarcophyton crassocaule, demonstrated cytotoxicity against cancer cell lines of human medulloblastoma (Daoy cells) where crassocolides I and M were found to be more active (IC₅₀ 0.8 and 1.1 μg/mL, respectively). Crassocolide H was also found to inhibit the growth of human oral epidermoid carcinoma (KB) cells (IC₅₀ 5.3 μg/mL) and crassocolide L active against human cervical epitheloid carcinoma (HeLa) cells (IC₅₀ 8.0 μg/mL) [].

Another example of a potential new therapeutic anticancer agent is a cembranolide diterpene from Lobophytum cristagalli, which has shown a potent inhibitory activity (IC₅₀ 0.15 μM) [59] over farnesyl protein transferase (FPT, an important protein in signal transduction and regulation of cell differentiation and proliferation []). This type of FPT inhibition enhanced interest in this group of metabolites [86]. Other species of this genus also showed cembranolide diterpenes (lobophytene) with significant cytotoxic activity against human lung adenocarcinoma (A549) and human colon adenocarcinoma (HT-29) cell lines []. Lobophytum durum and Lobophytum crassum produce durumolides A–C [60], durumhemiketalolide A–C [] and crassumolides A and C [], with anti-inflammatory effects. They have been shown to inhibit up-regulation of the pro-inflammatory iNOS and COX-2 proteins in LPS-stimulated murine macrophage cells at IC₅₀ < 10 μM [,60]. The diterpenoids, lobohedleolide, (7Z)-lobohedleolide, and 17-dimethylaminolobohedleolide, were isolated from the aqueous extract of Lobophytum species and exhibited moderate HIV-inhibitory activity (IC₅₀ approximately 7–10 μg/mL) in a cell-based in vitro anti-HIV assay []. Klyxum simplex produces diterpene compounds, such as simplexin E, which at a concentration of 10 μM was found to considerably reduce the levels of iNOS and COX-2 proteins to 4.8 ± 1.8% and 37.7 ± 4.7%, respectively. These results have shown that this compound significantly inhibits the accumulation of the pro-inflammatory iNOS and COX-2 proteins in LPS-stimulated RAW264.7 macrophage cells []. This species also produces two diterpene compounds, klysimplexins B and H, exhibiting moderate cytotoxicity towards human carcinoma cell lines. Klysimplexin B exhibits cytotoxicity toward human hepatocellular carcinoma (Hep G2 and Hep 3B), human breast carcinoma (MDA-MB-231 and MCF-7), human lung carcinoma (A549) and human gingival carcinoma (Ca9-22) cell lines with IC₅₀’s of 3.0, 3.6, 6.9, 3.0, 2.0, and 1.8 μg/mL, respectively. Metabolite klysimplexin H demonstrated cytotoxicity (IC₅₀’s 5.6, 6.9, 4.4, 5.6, 2.8 and 6.1 μg/mL) toward human hepatocellular carcinoma (Hep G2 and Hep 3B), human breast carcinoma (MDA-MB-231 and MCF-7), human lung carcinoma (A549) and human gingival carcinoma (Ca9-22) cell lines, respectively [55].

In Sinularia sp. (Figure 1A), a tetraprenylated spermine derivative has been isolated—sinulamide— which revealed an H,K-ATPase inhibitory activity. H,K-ATPase is a gastric proton pump of stomach and is the enzyme primarily responsible for the acidification of the stomach contents. Its inhibition is a very common clinical intervention used in diseases including dyspepsia, peptic ulcer, and gastroesophageal reflux (GORD/GERD). Sinulide is a potential antiulcer drug, as it inhibits production of gastric acid by H,K-ATPase (IC₅₀ 5.5 μM) [63]. Although it has been synthesized [100], no clinical trials seem to have been reported. The steroid gibberoketosterol [], isolated from Sinularia gibberosa, and the diterpenoid querciformolide C [] from Sinularia querciformis, showed significant inhibition of the up-regulation of the pro-inflammatory iNOS and COX-2 proteins in LPS-stimulated murine macrophages at concentration <10 μM [,]. Paralemnalia thyrsoides showed significant inhibition of pro-inflammatory iNOS protein expression (70% at IC₅₀ 10 μM) [101]. Sinularia species produce significant molecules: lipids from Sinularia grandilobata and another unspecified species of Sinularia possesses antibacterial and antifungal activity [64]. The diterpene 11-episinulariolide from Sinularia flexibilis is an interesting antifoulant exhibiting strong algacidal properties [66]. This species also produces cembrenoids, named flexilarins, which evidence cytotoxic activity in cancer cell lines. Flexilarin D exhibited potent cytotoxicity in human hepatocarcinoma (Hep2) cells with IC₅₀ 0.07 μg/mL, and moderate cytotoxic activity against human cervical epitheloid carcinoma (HeLa, IC₅₀ 0.41 μg/mL), human medulloblastoma (Daoy, 1.24 μg/mL) and human breast carcinoma (MCF-7, 1.24 μg/mL) cell lines [65].

Antifouling agents from natural sources are of increasing interest since the International Maritime Organization (IMO) banned the use of certain antifouling agents, such as tri-n-butyltin (TBT), due to the ecological impacts of these biocides in the marine environment. Several studies have demonstrated that soft corals can yield large quantities of promising antifouling metabolites [102,103]. In fact, 17.95% of potential antifouling natural compounds are from cnidarians (e.g., soft coral) [104]. One of the most promising natural antifouling agent identified so far is an isogosterone isolated from an unspecified Dendronephthya [77].

The genus Clavularia contains secondary metabolites with unique structures and remarkable biological activities. Some of the species in this genus produce prostanoids (icosanoids) [,105,], steroids [] and diterpenoids [,107]. The bioactive marine diterpene, stolonidiol, isolated from an unidentified Clavularia, showed potent choline acetyltransferase (ChAT) inducible activity in primary cultured basal forebrain cells and clonal septal SN49 cells, suggesting that it may act as a potent neurotrophic factor-like agent on the cholinergic nervous system []. Cholinergic neurons in the basal forebrain innervate the cortex and hippocampus, and their function may be closely related to cognitive function and memory. The degeneration of neuronal cells in this brain region is considered to be responsible for several types of dementia including Alzheimer’s disease. One of the neurotransmitters, acetylcholine, is synthesized from acetyl coenzyme A and choline by the action of ChAT. Therefore, induction of ChAT activity in cholinergic neurons may improve the cognitive function in diseases exhibiting cholinergic deficits [–].

Prostanoids (claviridic acid) isolated from Clavularia viridis exhibited potent inhibitory effects on phytohemagglutinin-induced proliferation of peripheral blood mononuclear cells (PBMC, 5 μg/mL), as well as significant cytotoxic activity against human gastric cancer cells (AGS, IC₅₀ 1.73–7.78 μg/mL) []. Claviridenone extracts also showed potent cytotoxicity against mouse lymphocytic leukemia (P-388) and human colon adenocarcinoma (HT-29), and exceptionally potent cytotoxicty against human lung adenocarcinoma (A549) cells, with ED₅₀ between 0.52 pg/mL and 1.22 μg/mL []. Halogenated prostanoids also showed cytotoxic activity against human T lymphocyte leukemia cells (MOLT-4, IC₅₀ 0.52 μg/mL), human colorectal adenocarcinoma (DLD-1, IC₅₀ 0.6 μg/mL) and human diploid lung fibroblast (IMR-90, IC₅₀ 4.5 μg/mL) cells []. The cyclopentenone prostanoid, bromovulone III-a promising marine natural compound for treatment of prostate, colon and hepatocellular carcinoma-showed anti-tumor activity against human prostate (PC-3) and human colon (HT29) cancer cells at an IC₅₀ of 0.5 μM [], and induced apoptotic signaling in a sequential manner in Hep3B cells []. In the case of prostate cancer cells, this compound displayed an anti-tumor activity 30 to 100 times more effective than cyclopentenone prostaglandins (known to suppress tumor cell growth and to induce apoptosis in prostate cancer cells), by causing a rapid redistribution and clustering of Fas (member of the tumor necrosis factor (TNF) receptor superfamily). Apoptotic stimulation of Fas by specific ligand or antibodies causes the formation of a membrane-associated complex comprising Fas clustering) in PC-3 cells []. C. viridis also produces steroids that show cytotoxic activity against human colorectal adenocarcinoma (DLD-1, 0.02 < IC₅₀ < 50 μg/mL) and also against human T lymphocyte leukemia cells (MOLT-4, 0.01 < IC₅₀ < 10 μg/mL), in the case of yonarasterols []. Stoloniferone additionally displayed potent cytotoxicity against mouse lymphocytic leukemia (P-388), human colon adenocarcinoma (HT-29) and human lung adenocarcinoma (A549) cells []. This species produces several compounds with anti-tumor activity in different types of human tumors, although more in vitro studies are needed to determine which compound are potential anticancer agents. Clavularia koellikeri produces diterpenoids as secondary metabolites, which display cytotoxic activity against human colorectal adenocarcinoma (DLD-1, IC₅₀ 4.2 μg/mL) and strong growth inhibition against human T lymphocyte leukemia cells (MOLT-4, IC₅₀ 0.9 μg/mL) [].

In the genus Cespitularia, several interesting diterpenes of cembrane and neodolabellane skeletons have been identified. In Cespitularia hypotentaculata (family Xeniidae) a significant production of diterpenoids was detected. Cespitularin C exhibited potent cytotoxicity against mouse lymphocytic leukemia (P-388, ED₅₀ 0.01 μg/mL) and human lung adenocarcinoma (A549, ED₅₀ 0.12 μg/mL) cells, while cespitularin E exhibited potent cytotoxicity against human lung adenocarcinoma (A549, ED₅₀ 0.034 μg/mL) cell cultures []. A less active diterpene, Asterolaurin A, from Asterospicularia laurae (a species from the same family) exhibited cytotoxicity against human hepatocellular carcinoma (HepG2) cells with an IC₅₀ 8.9 μM [].

Telesto riisei produces punaglandins, highly functional cyclopentadienone and cyclopentenone prostaglandins. Cyclopentenone prostaglandins have unique antineoplastic activity and are potent growth inhibitors in a variety of cultured cells. These punaglandins have been shown to inhibit P53 accumulation (a tumor suppressor protein) and ubiquitin isopeptidase activity (IC₅₀ between 0.04 and 0.37 μM) (enzyme involved in protein degradation system) in vitro and in vivo []. Since these proteasome inhibitors exhibit higher antiproliferative effects than other prostaglandins [], they may represent a new class of potent cancer therapeutics.

3.2. Order Gorgonacea (Sea Fans)

Gorgonians are a well-known source of compounds exhibiting significant biological activity []. Table 3 summarizes the most promising compounds from order Gorgonacea (class Anthozoa) described in the present review. Studies on Isis hippuris have resulted in the isolation of a series of novel metabolites such as sesquiterpenes [], steroids [115], A-nor-hippuristanol [116] and isishippuric acid B [116]. These compounds exhibit potent cytotoxicity against cancer cell lines of human hepatocellular carcinoma (HepG2 and Hep3B, IC₅₀ 0.08–4.64 μg/mL and 0.10–1.46 μg/mL, respectively) [116,], human breast carcinoma (MCF-7, IC₅₀ 0.20–4.54 μg/mL and MDA-MB-231, IC₅₀ 0.13–2.64 μg/mL) [], mouse lymphocytic leukemia (P-388), human lung adenocarcinoma (A549), and human colon adenocarcinoma (HT-29) with ED₅₀ values less than 0.1 μg/mL [115,116] and IC₅₀ of 0.1 μg/mL [].

Table 3

Most promising compounds studied in the last decade from cnidarian species in order Gorgonacea (sea fans), class Anthozoa.

ND: Not Determined; BHS: Bahamas; COL: Colombia; GEO: Georgia; IND: Indonesia; PAN: Panama; TAIW: Taiwan; USA: United States of America.

Species from the genus Pseudopterogorgia are a rich source of unusual biologically active diterpenoids, sesquiterpenes, and polyhydroxylated steroids, which exhibit diverse structures [127,140,]. A sample of the organic extract of Pseudopterogorgia bipinnata was included in an initial screening carried out as part of an effort in the discovery of new antimalarial agents. This extract was found to be active in inhibiting the growth of Plasmodium falciparum (a protozoan parasite responsible for the most severe forms of malaria). Caucanolide A and D demonstrated significant in vitro antiplasmodial activity against chloroquine-resistant P. falciparum W2 (IC₅₀ 17 μg/mL and IC₅₀ 15 μg/mL, respectively) []. Three secosterols isolated from an unidentified gorgonian from genus Pseudopterogorgia inhibited human protein kinase C (PKC) α, βI, βII, γ, δ, ɛ, η, and ζ, with IC₅₀ values in the range 12–50 μM [125]. PKC is a key player in cellular signal transduction and has been implicated in cancer, cardiovascular and renal disorders, immunosuppression, and autoimmune diseases such as rheumatoid arthritis []. Semisynthetic derivatives also showed a similar activity [125]. Promising antimicrobial substances were also reported from Pseudopterogorgia rigida (e.g., curcuphenol) [136] and from Pseudopterogorgia elisabethae (e.g., pseudopterosin X and Y) [129]. Ileabethoxazole, homopseudopteroxazole, caribenols A and B and elisapterosin B from P. elisabethae and bipinnapterolide B from P. bipinnata inhibit Mycobacterium tuberculosis H₃₇Rv at a concentration of 12.5 μg/mL [,] (for elisapterosin B and homopseudopteroxazole) and at a concentration range of 128–64 μg/mL [130,142] (for others compounds). In fact, the inhibition of M. tuberculosis H₃₇Rv is within the ranges recorded for rifampin [130]. P. elisabethae and P. bipinnata also produce antituberculosis compounds. Bielschowskysin, a naturally occurring diterpene isolated from Pseudopterogorgia kallos [] and aberrarone isolated from P. elisabethae [] exhibited antiplasmodial activity (IC₅₀ 10 μg/mL) when tested against P. falciparum. The first compound was also found to display strong and specific in vitro cytotoxicity against the EKVX non-small cell lung cancer (GI₅₀ < 0.01 μM) and CAKI-1 renal cancer (GI₅₀ 0.51 μM) []. Bis(pseudopterane) amine from Pseudopterogorgia acerosa was found to exhibit selective activity against HCT116 (IC₅₀ 4 μM) cell lines [].

Fuscosides, originally isolated from Eunicea fusca [138], selectively and irreversibly inhibited leukotriene synthesis. Leukotrienes are molecules of the immune system that contribute to inflammation in asthma and allergic rhinitis and its production is usually related to histamine release []. Pharmacological studies indicated that fuscoside B inhibits the conversion of arachidonic acid (AA) to leukotriene B₄ and C₄ (LTB₄ and LTC₄) [138,] by inhibiting the 5-Lipoxygenase (5-LO), in the case of LTB₄ with an IC₅₀ of 18 μM []. These selective inhibitors of lipoxygenase isoforms can be useful as pharmacological agents, as nutraceuticals or as molecular tools []. Sesquiterpenoids metabolites isolated from Eunicea sp. display antiplasmodial activity against the malaria parasite P. falciparum W2 (chloroquine-resistant) strain, with IC₅₀ values ranging from 10 to 18 μg/mL [].

The gorgonian Junceella fragilis produces secondary metabolites, frajunolides B and C, with anti-inflammatory effects towards superoxide anion generation and elastase release by human neutrophils, with an IC₅₀ > 10 μg/mL [121]. When properly stimulated, activated neutrophils secrete a series of cytotoxins, such as the superoxide anion (O₂^·−), a precursor of other reactive oxygen species (ROS), granule proteases, and bioactive lipids [,]. The production of the superoxide anion is linked to the killing of invading microorganisms, but it can also directly or indirectly damage surrounding tissues. On the other hand, neutrophil elastase is a major secreted product of stimulated neutrophils and a major contributor to the destruction of tissue in chronic inflammatory disease []. The anti-inflammatory butenolide lipide [] from the gorgonian Euplexaura flava [139] can be currently synthesized, opening the possibility of advancing into a new level of anti-inflammatory pharmaceuticals.

Some of the most interesting compounds identified so far in the on-going search for new anti-fouling agents have been recorded in the order Gorgonacea. Good examples of such compounds are juncin ZII from Junceella juncea [122], homarine from Leptogorgia virgulata and Leptogorgia setacea [], pukalide and epoxypukalide recorded so far only from L. virgulata [].

Species of genus Briareum (family Briareidae) (Figure 1D) (which commonly exhibit an incrusting appearance rather than the fan-like shape of many gorgonians) are widely abundant in Indo-Pacific and Caribean coral reefs. These organisms have been recognized as a valuable source of bioactive compounds with novel structural features. Briarane-related natural products are a good example of such promising compounds due to their structural complexity and biological activity [149,150]. Briaexcavatin E, from Briareum excavata (Nutting 1911), also occasionally referred to as Briarium excavatum, inhibited human neutrophil elastase (HNE) release with an IC₅₀ between 5 and 10 μM [118]. Briaexcavatolides L and P, diterpenoids from the same species exhibited significant cytotoxicity against mouse lymphocytic leukemia (P-388) tumor cells with ED₅₀ of 0.5 [] and 0.9 μg/mL [], respectively. Diterpenoids produced from Briareum polyanthes (presently accepted as Briareum asbestinum), namely Briarellin D, K and L, exhibited antimalarial activity against P. falciparum with an IC₅₀ between 9 and 15 μg/mL [].

3.3. Other Orders

Sea anemones (order Actiniaria) are a rich source of biologically-active proteins and polypeptides. Several cytolytic toxins, neuropeptides and protease inhibitors have been identified from them []. In addition to several equinatoxins, potent cytolytic proteins and an inhibitor of papain-like cysteine proteinases (equistatin), were isolated from the sea anemone Actinia equina []. Equistatin has been shown to be a very potent inhibitor of papain and a specific inhibitor of the aspartic proteinase cathepsin D []. While papain-like cysteine proteases have been implicated in various diseases of the central nervous system, such as brain tumors, Alzheimer’s disease, stroke, cerebral lesions, neurological autoimmune diseases and certain forms of epilepsy [154], aspartic proteinase cathepsin D is involved in the pathogenesis of breast cancer [] and possibly Alzheimer’s disease [156].

Cycloaplysinopsin C, a bis(indole) alkaloid isolated from Tubastrea sp. (order Scleractinia), was found to inhibit growth of two strains of P. falciparum, one chloroquine-sensitive (F32/Tanzania) and other chloroquine-resistant (FcB1/Colombia) with IC₅₀ 1.48 and 1.2 μg/mL, respectively []. Cladocorans A and B, isolated from Cladocora caespitosa (order Scleractinia) [49], are marine sesterterpenoids which possess a γ-hydroxybutenolide moiety, which is thought to be responsible for the biological activity of these compounds. The potent anti-inflammatory activity of these natural metabolites was attributed to the inhibition of secretory phospholipase A₂ (sPLA₂, IC₅₀ 0.8–1.9 μM). Given the general role of inflammation in diseases that include bronchial asthma and rheumatoid arthritis, identifying and developing potent inhibitors of sPLA2 continues to be of great importance for the pharmaceutical industry, with this type of metabolite being of paramount importance for future research [].

4. Class Hydrozoa

Class Hydrozoa includes seven orders and nearly 3500 valid species (Table 1), some of which are solitary, some of which are colonial. Among the most emblematic species are probably hydroids and the Portuguese man-o-war (Physalia physalis). Despite the large number of species in class Hydrozoa, only a few of them have yielded interesting MNPs in the last decade.

Immune escape plays an important role in cancer progression and, although not completely understood, it has been proposed that indoleamine 2,3-dioxygenase (IDO) plays a central role in evasion of T-cell-mediated immune rejection []. IDO catalyzes the oxidative cleavage of the 2,3 bond of tryptophan, which is the first and rate-limiting step in the kynurenine pathway of tryptophan catabolism in mammalian cells []. The polyketides annulins A, B, and C, purified from the marine hydroid Garveia annulata (order Anthoathecata), potently inhibited IDO in vitro (K_i 0.12–0.69 μM) []. These annulins are more powerful than most tryptophan analogues known to be IDO inhibitors. These compounds are active at concentrations higher than ~10 μM and therefore more effective than 1-methyltryptophan (K_i 6.6 μM), one of the most potent IDO inhibitors currently available []. Solandelactones C, D, and G are cyclopropyl oxylipins isolated from the hydroid Solanderia secunda (order Anthoathecata) and exhibit moderate inhibitory activity against farnesyl protein transferase (FPT, 69, 89, and 61% inhibition, respectively) at a concentration of 100 μg/mL [161]. Note that FPT is associated with cell differentiation and proliferation and its inhibition may be a target for novel anticancer agents (as already referred above for the soft coral L. cristagalli).

5. Class Scyphozoa

Approximately 200 species are currently classified in three orders in class Scyphozoa (Table 1). However, in the last decade, only a single MNP purified from the mesoglea of the jellyfish Aurelia aurita (order Semaeostomeae) was considered to be promising enough to be included in the present work. This compound is a novel endogenous antibacterial peptide, aurelin, which exhibited activity against Gram-positive and Gram-negative bacteria. As an example, aurelin displayed an IC₅₀ of 7.7 μg/mL for Esherichia coli (Gram negative bacteria) [].

6. Other Classes

The classes Staurozoa, Cubozoa and Polypodiozoa are the least speciose in the phylum Cnidaria (Table 1). This fact may explain the current lack of data on secondary metabolites produced by these organisms. It is possible that with growing bioprospecting new MNPs may be revealed once these cnidarian species are screened. Cubozoa (box jellies), for example, produce some of the most harmful cnidarian toxins for humans [].

7. Exploring the Unexplored and Being Creative: Future Perspectives for the Bioprospecting of Cnidarians

For several years, the bioprospecting of cnidarians was commonly limited to habitats that could be readily sampled by researchers, such as shallow coral reefs and the intertidal region. However, with improvements in SCUBA gear, researchers are now able to dive deeper and longer, allowing them to collect a wider range of cnidarian species for the screening of MNPs. The growing efforts to explore Earth’s last frontier, the deep sea, made it possible to start bioprospecting several unique marine ecosystems that had remained either previously unrecorded or inaccessible to researchers [164]. New cnidarian species (some of them belonging to new genera and probably even to new families) (e.g., [165,166]) are currently being sampled from the deep sea. These findings suggest that many new species are yet to be discovered along deep continental margins [167] and open good perspectives for the discovery of new MNPs with ongoing surveys of deep sea fauna. Cnidarians are known to colonize unique deep sea biotopes, namely chemosynthetic sites (such as hydrothermal vents, cold seeps and whale falls []), as well as seamounts [169]. Some of these organisms are endemic to these habitats and display remarkable adaptations to extreme environments (e.g., chemosynthetic sea anemones) []. These species are certainly interesting candidates for the discovery of new MNPs []. However, some of these remarkable biotopes, namely deep sea coral reefs, are already facing serious threats to their conservation [169] and thus, the bioprospecting of these and other endangered habitats must be carefully addressed [164,].

Another interesting source of cnidarian species for bioprospecting is the marine aquarium industry. Over 200 species of hard and soft corals, along with several other anemone, zoanthid and corallimorph species, are harvested every year from coral reefs to supply the marine aquarium trade [173]. However, researchers using these organisms in the bioprospecting of new MNPs must be aware that it is not commonly possible to get reliable information on either the place of origin or the scientific name of most traded specimens. With the advent of high-throughput screening (HTS) [], it will be possible to rapidly survey these organisms for interesting MNPs, although HTS of natural sources may present several challenges (see [,]). If necessary, additional biomass of target organisms producing interesting MNPs can be achieved using inexpensive techniques [177,178] and eliminate problems commonly faced by researchers screening marine organisms for MNPs–the loss of the source and reproducibility [].

The discovery of a new compound commonly requires only small amounts of biomass. However the production of these compounds at a scale large enough to fulfill commercial applications is still nearly impossible []. In theory, large-scale production of bioactive compounds can be achieved by chemical synthesis or through extraction from marine animals, either harvested from the sea or maricultured. The existence of ecophysiological diversity (e.g., differences between individuals often due to differences in environmental interactions) can interfere with the production of MNPs and must be carefully addressed in future efforts for large-scale production of these compounds. The harvest of target animals from the wild for the production of chemical compounds is commonly an unsustainable solution, while mariculture has proven to be more technically challenging and expensive than previously assumed []. In other considerations, chemical synthesis is not yet developed to synthesize complex molecules at the kilogram scale and, in cases where this may already be technically possible, most of the compounds cannot be synthesized at a price affordable for commercial applications []. Potential solutions for such bottlenecks may be the use of diverted total synthesis [] and/or metabolic engineering [].

There is growing evidence that microbes associated with marine invertebrates may be the true producers of some of the bioactive compounds isolated from these animals []. Whether this is the case of bioactive compounds currently assumed to be produced by cnidarians remains unanswered [,]. If so, we face another constraint for the commercial use of these compounds, as the culture of symbiotic microorganisms is generally not possible using classic/standardized methodologies.

8. Conclusions

The intense pressure to find and develop more profitable molecules for all sorts of industries continues to fuel the bioprospecting of marine invertebrates. Although the phylum Cnidaria is not the most significantly bioprospected at present, this review shows that some cnidarian species are promising sources of marine bioactive compounds of medical, economic and scientific interest. Green fluorescent protein (GFP), GPF-like proteins, red fluorescent and orange fluorescent protein (OPF) are good examples of biotechnological metabolites currently employed as molecular biomarkers. They were first purified from a fluorescent hydrozoan medusa [] and since then have been recorded in other cnidarian species [–].

In the present survey, only about 0.31% of extant cnidarian species are represented, with class Anthozoa displaying by far the highest number of promising MNPs (Figure 2). This result is probably due to the fact that this class is the most speciose in the phylum (Table 1). Additionally, many anthozoans occupy marine habitats which can be readily accessed for the collection of biomass (e.g., coral reefs and intertidal regions), which facilitates bioprospecting. Of all the compounds presented in this review, 84% were detected in cnidarians collected from tropical waters (mostly from Southeast Asia and the Caribbean Sea) and the remaining 16% were recorded from species mostly occupying temperate waters (e.g., European countries and Japan).

Marine bioactive compounds with high biotechnological potential studied from the phylum Cnidaria in the last decade.

Antitumor drugs are the main area of interest in the screening of MNPs from cnidarians (41%, Figure 3). This is not surprising, as the major financial effort for the screening of new marine compounds is made in cancer research [192]. Terpenoids (terpenoid, diterpenoid, sesquiterpenoid, sesterterpenoid, cembranoid) [193] (Figure 4) are the main chemistry group within the MNPs analyzed in this survey.

Distribution in drug classes of marine bioactive compounds with high biotechnological potential studied from cnidarian species in the last decade.

Distribution of chemistry classes of marine bioactive compounds with high biotechnological potential studied from cnidarian species in the last decade.

Even though most pharmaceutical industries abandoned their natural product-based discovery programs over a decade ago, the lack of new compounds in their pipelines in some strategic areas (e.g., antibiotics) suggests that renewed interest in this field is imminent. The establishment of small biotech companies can play a decisive role in the initial discovery of promising marine bioactive compounds, as these enterprises will work closely together with academics and governmental agencies performing the initial steps in the discovery of new MNPs. Collaboration between private companies and public institutions can be of paramount importance for financial support in the discovery process. On the other side, crude extracts and pure compounds produced by academic laboratories may be screened by diverse bioassays as a part of broader collaboration programs, nationally and internationally, with private biotech companies. One challenge for universities is to devise mechanisms that protect intellectual property and simultaneously encourage partnerships with the private sector, by recognizing that the chances of a major commercial pay-off are small if drug discovery is pursued by a single institution [].

The commercial use of some promising marine bioactive compounds isolated from cnidarians may be several years away. New compounds other than toxins and venoms produced by members of this highly diverse group of marine invertebrates may be discovered in the quest for new marine products.

Acknowledgements

Joana Rocha is supported by a Fundação para a Ciência e Tecnologia PhD Grant (SFRH/BD/33476/ 2008) by PhD Program in Marine and Environmental Sciences. This research was partially financed by project LUSOEXTRACT (project no. 13107, QREN-SI I&DT, co-promotion and co-financed by POR Lisboa, AdI). The authors would like to acknowledge one anonymous reviewer and Daphne Fautin for their valuable comments on the manuscript.

References

Associated Data

Abstract

Introduction

The Fibromyalgia Impact Questionnaire (FIQ) is a commonly used instrument in the evaluation of fibromyalgia (FM) patients. Over the last 18 years, since the publication of the original FIQ, several deficiencies have become apparent and the cumbersome scoring algorithm has been a barrier to widespread clinical use. The aim of this paper is to describe and validate a revised version of the FIQ: the FIQR.

Methods

The FIQR was developed in response to known deficiencies of the FIQ with the help of a patient focus group. The FIQR has the same 3 domains as the FIQ (that is, function, overall impact and symptoms). It differs from the FIQ in having modified function questions and the inclusion of questions on memory, tenderness, balance and environmental sensitivity. All questions are graded on a 0–10 numeric scale. The FIQR was administered online and the results were compared to the same patient's online responses to the 36-Item Short Form Health Survey (SF-36) and the original FIQ.

Results

The FIQR was completed online by 202 FM patients, 51 rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) patients (31 RA and 20 SLE), 11 patients with major depressive disorder (MDD) and 213 healthy controls (HC). The mean total FIQR score was 56.6 ± 19.9 compared to a total FIQ score of 60.6 ± 17.8 (P < 0.03). The total scores of the FIQR and FIQ were closely correlated (r = 0.88, P < 0.001). Each of the 3 domains of the FIQR correlated well with the 3 related FIQ domains (r = 0.69 to 0.88, P < 0.01). The FIQR showed good correlation with comparable domains in the SF-36, with a multiple regression analysis showing that the three FIQR domain scores predicted the 8 SF-36 subscale scores. The FIQR had good discriminant ability between FM and the 3 other groups; total FIQR scores were HC (12.1 ± 11.6), RA/SLE (28.6 ± 21.2) and MDD (17.3 ± 11.8). The patient completion time was 1.3 minutes; scoring took about 1 minute.

Conclusions

The FIQR is an updated version of the FIQ that has good psychometric properties, can be completed in less than 2 minutes and is easy to score. It has scoring characteristics comparable to the original FIQ, making it possible to compare past FIQ results with future FIQR results.

Introduction

The Fibromyalgia Impact Questionnaire (FIQ) was developed in the late 1980s and was first published in 1991 [], with minor revisions in 1997 and 2002 []. It has subsequently become one of the most frequently used tools in the evaluation of fibromyalgia (FM) patients [-], being cited in over 300 articles and translated into 14 languages. Over the 18 years since its publication, problems in regard to some aspects of its content and rather cumbersome scoring algorithm have become apparent [-6]. The original questionnaire used a visual analog scale (VAS) that required patients to slash a 100-mm line and was scored with a ruler. The scoring was further complicated by the need to reverse scores in one question and the use of constants to convert the first 13 questions to a standardized scale of 0 to 10. The functional questions in the first part of the FIQ were originally intended for women living in reasonably affluent countries and assumed the possession of a car, a vacuum cleaner, and a washing machine. Moreover, questions that now are considered relevant, such as dyscognition, tenderness, balance, and environmental sensitivity, were not part of the original FIQ. With these issues in mind, we have developed an online and paper-equivalent version of the questionnaire: the Revised Fibromyalgia Impact Questionnaire (FIQR) (Additional data file 1). The FIQR attempts to address the limitations of the FIQ while retaining the essential properties of the original instrument.

Materials and methods

Focus group testing

A draft version of the new questionnaire was constructed by RMB and tested in a focus group of 10 female patients with FM (age 58 ± 5.4 years, age range 51 to 68 years; FM duration 22 ± 12.7 years, duration range 3 to 40 years). The focus group was guided by RMB with the assistance of KDJ, RLR, and RW. It was conducted in a manner that encouraged the free interchange of ideas. The revised questions were based on previous experience with the FIQ and patients' evaluation of important symptoms as recorded in OMERACT 8 (Outcome Measures in Rheumatology) [], International Classification of Functioning, Disability, and Health (ICF) guidelines [8], and patient surveys from the US [] and Germany []. The draft modifications of the original FIQ were sixfold: (a) perform all scoring with 11 boxes (scaled 0 to 10) instead of a mixture of Likert measurements and VAS measurements; (b) modify the functional questions (numbers 1 to 11 in the original FIQ); (c) modify the two impact questions (numbers 12 and 13 in the original FIQ); (d) expand the symptom questions (numbers 14 to 20 in the original FIQ) to include tenderness, dyscognition, balance, and environmental sensitivity; (e) simplify the scoring algorithm; and (f) modify the weighting of the three domains (function, overall impact, and symptoms) to give more weight to function. The proceedings were digitally recorded and transcribed by RW. Following a discussion among patients and investigators, modifications were made to the draft version of the FIQR and agreement was reached on the final version of the FIQR (Table ​(Table1).1). For instance, an original FIQ question regarding 'walking several blocks' was modified by the focus group to 'walk continuously for 20 minutes' as the concept of a block varies from city to city and country to country. The entirely new question, 'sit in a chair for 45 minutes', arose out of a discussion on problems associated with pain and immobility. As it was intended to conduct the validation of the FIQR online, the use of this collection method and the validity of using 11 boxes rather than 0- to 100-mm VASs were compared between the following five versions of the questionnaires that were completed by the focus group: (a) the original paper version of the FIQ (FIQ-P), (b) an online version of the FIQ (FIQ-OL), (c) a paper version of the FIQR using 11 boxes scaled 0 to 10 (FIQR-P), (d) a paper version of the FIQR using a 100-mm VAS scoring (FIQR-P VAS), and (e) an online version of the FIQR (FIQR-OL). The online versions of the FIQR and FIQ were completed 4 weeks after completion of the paper versions.

Table 1

Scoring: Step 1. Sum the scores for each of the three domains (function, overall, and symptoms). Step 2. Divide domain 1 score by three, divide domain 2 score by one (that is, it is unchanged), and divide domain score 3 by two. Step 3. Add the three resulting domain scores to obtain the total Revised Fibromyalgia Impact Questionnaire score.

The Revised Fibromyalgia Impact Questionnaire and its scoring

The revised FIQ (the FIQR) has 21 individual questions (Table ​(Table1).1). All questions are based on an 11-point numeric rating scale of 0 to 10, with 10 being 'worst'. As in the FIQ, all questions are framed in the context of the past 7 days. Following the convention used in the FIQ, the FIQR is divided into three linked sets of domains: (a) 'function' (contains 9 questions versus 11 in the FIQ), (b) 'overall impact' (contains 2 questions, as in the FIQ) but the questions now relate to the overall impact of FM on functioning and the overall impact symptom severity, and (c) 'symptoms' (contains 10 questions versus 7 in the FIQ); one original FIQ symptom was dropped: 'When you worked, how much did pain or other symptoms of your fibromyalgia interfere with your ability to do your work, including housework?' The symptom domain contains four new questions relating to memory, tenderness, balance, and environmental sensitivity (to loud noises, bright lights, odors, and cold temperatures). The 'time' dimension is the same as the FIQ; that is, all questions relate to the impact of FM over the course of the past 7 days. The scoring of the FIQR is much simpler than the FIQ: namely, the summed score for function (range 0 to 90) is divided by 3, the summed score for overall impact (range 0 to 20) is not changed, and the summed score for symptoms (range 0 to 100) is divided by 2. The total FIQR is the sum of the three modified domain scores. The weighting of these three domains is different from the FIQ in that 30% of the total score is ascribed to 'function' as opposed to 10% in the FIQ, 50% is ascribed to 'symptoms' as opposed to 70% in the FIQ, and 'overall impact' remains the same as the FIQ at 20%. The total maximal score of the FIQR remains the same as the FIQ, namely 100.

Subjects

All of the FM subjects were patients diagnosed within the previous 5 years with FM as defined by the American College of Rheumatology (ACR) []. They had indicated that they were interested in being contacted in regard to FM research studies. The patients with either rheumatoid arthritis or systemic lupus erythematosus (RA/SLE) were all patients being currently treated and followed in the clinical practice of BKH; patients with coexisting FM were excluded initially by prescreening the patient charts for a diagnosis of FM and then re-evaluating each subject prior to entry into the study. The patients with major depressive disorder (MDD) were all patients being currently treated and followed in the clinical practice of RLR; patients with coexisting FM were excluded as above. The healthy control group consisted of coworkers, friends, and relatives; they were requested to email the questionnaire link to acquaintances whom they considered to be in good health. All participants completed online informed consent, and the study was conducted in accordance with the Declaration of Helsinki.

Data collection

The questionnaires were formatted for use on Survey Monkey (Portland, OR, USA), a commercial online survey technology. In addition to the FIQR, the original questionnaire (FIQ) and the 36-Item Short Form Health Survey (SF-36) (Rand Corporation, Santa Monica, CA, USA) were posted on the Survey Monkey site for the FM subjects. The SF-36 is a widely used generic instrument that measures health-related quality of life [] and has a well-documented use in the evaluation of FM patients [,]. The online site for the healthy controls and RA, SLE, and MDD subjects did not contain the FIQ or SF-36 questionnaire. The questionnaire for healthy controls and RA, SLE, and MDD patients differed from the questionnaire for FM patients in that the term 'health issues' was substituted throughout the questionnaire for 'fibromyalgia' (this questionnaire, the SIQR, is available in the online version of this article; Additional data file 2). To ascertain that FM subjects still had widespread pain and that the healthy controls and RA, SLE, and MDD patients did not have widespread pain, the questionnaire contained a 'yes/no' item as to the body areas in which they currently had pain. This item contained 24 separate locations: left shoulder, right shoulder, left jaw, right jaw, left upper back, right upper back, left arm, right arm, left hand, right hand, left lower back, right lower back, left hip, right hip, left thigh, right thigh, left knee, right knee, left foot, right foot, mid upper back, mid lower back, front of chest, and neck.

The survey was sent out to 659 FM patients in August 2008, and 208 responded within 2 weeks (a response rate of 32%). After approximately 200 FM subjects had completed the questionnaire, the results were downloaded from the Survey Monkey server into Excel spreadsheets (Microsoft Corporation, Redmond, WA, USA) and the survey was closed to further participation for the FM patients. The RA/SLE and the MDD sites were kept open for about 3 months as it was challenging to find RA, SLE, and MDD patients who did not have widespread pain. The FIQR scoring algorithm was processed on the Excel spreadsheet and then transferred to STATISTICA statistical software (StatSoft, Inc., Tulsa, OK, USA) for the statistical analyses. As a check on data entry and scoring, the Excel spreadsheet was also loaded into version 14 of SPSS statistical software (SPSS Inc., Chicago, IL, USA) and the scoring algorithm was entered into SPSS syntax. Correlation and verification of the STATISTICA data and results were performed by RW and KDJ.

Data analysis

All data were analyzed in STATISTICA (version 8). Item analysis and questionnaire properties, including domain characteristics, were evaluated using basic statistics, reliability item analysis, and Cronbach alpha. Group comparisons on the mean total FIQR scores and individual FIQR items used one-way analysis of variance (ANOVA) and multivariate ANOVA for single and multiple dependent variables, respectively, with Tukey honestly significantly differences (HSD) post hoc analyses for unequal sample sizes comparing the significance of specific means. FIQR validity was established using correlational analyses between FIQR, FIQ, and SF-36 items and domains. Correlations were assessed using Pearson's product moment correlation coefficient (r). Multiple regression was used to establish convergent and discriminant validity. The three FIQR domains were entered simultaneously as predictors to determine their combined contribution of variance in SF-36 subscales. Standardized regression coefficients (β) were calculated to evaluate the unique contribution of the three FIQR domains to the SF-36 subscales, and the partial correlation coefficients (pr) were calculated to determine the correlation of each of the three FIQR domains to the SF-36 subscales after controlling for the other two domains.

Results

Focus group

The focus group tested the relatedness of two versions of the FIQ (FIQ-P and FIQ-OL) versus three versions of the FIQR (FIQR-P, FIQR-P VAS, and FIQR-OL). Converting the FIQ to an online questionnaire did not significantly affect its total mean scores (59.8 versus 61.8) (Table ​(Table2).2). The use of 11 boxes rather than 0- to 100-mm VASs did not significantly affect the total mean scores of the paper version of the FIQR (56.4 versus 57.6). Finally, the online version of the FIQR had a total score similar to that of the paper version of the FIQ (59.7 versus 59.8), with a correlation coefficient of 0.83 (P < 0.005). These results provided some confidence that an online version of the FIQR, with 11-box scoring (0 to 10), would probably have operating characteristics similar to those of the well-validated paper version of the original questionnaire (FIQ) that uses VAS scoring. As the online versions were completed 4 weeks after the paper versions, the similarity of scoring and correlations of the respective paper and online scores provide some evidence for test-retest reliability.

Table 2

Focus group total scores and correlations of the various versions of the Fibromyalgia Impact Questionnaire and the Revised Fibromyalgia Impact Questionnaire

All correlations were significant at P < 0.001. FIQ-OL, an online version of the Fibromyalgia Impact Questionnaire; FIQ-P, the original paper version of the Fibromyalgia Impact Questionnaire; FIQR-OL, an online version of the Revised Fibromyalgia Impact Questionnaire; FIQR-P, a paper version of the Revised Fibromyalgia Impact Questionnaire using 11 boxes scaled 0 to 10; FIQR-P VAS, a paper version of the Revised Fibromyalgia Impact Questionnaire using a 100-mm visual analog scale scoring instead of 11 boxes; SD, standard deviation.

The focus group also completed the SF-36 to compare ease of use and timing. During the focus group meeting, the FM patients contributed to the face validity of the final version by suggesting modifications in wording. For instance, the original FIQ question regarding 'walking several blocks' was reworded to 'walk continuously for 10 minutes', 'climb stairs' was modified to 'climb one flight of stairs', 'make beds' was modified to 'change bed sheets', 'do shopping' was modified to 'go shopping for groceries', and 'vacuum a rug' was modified to 'vacuum, scrub, or sweep floors'. The focus group also suggested two new questions: 'brush or comb your hair' and 'sit in a chair for 45 minutes'. The 'brush or comb hair' was to be the first question in the 'function' set as it is usually the least problematic activity for FM patients and would set the difficulty level for the following eight questions. The results from this focus group helped to provide some confidence that it would be feasible to use online data collection in that converting the 0- to 100-mm VASs and the Likert questions from the FIQ to an 11-point numeric rating scale (0 to 10) would not appreciably compromise the comparison of the FIQR with the FIQ. Patient completion times for the paper versions of the original FIQ, the FIQR, and the SF-36 were 2.1 ± 0.03 minutes, 1.3 ± 0.02 minutes, and 4.1 ± 0.04 minutes, respectively. The time taken for investigator scoring of the FIQR was approximately 1 minute.

Analysis of Revised Fibromyalgia Impact Questionnaire properties

A total of 208 FM patients completed the online questionnaires (FIQR, FIQ, and SF-36). There were 21 FM subjects who had fewer than 10 pain locations; on further review of their pain distribution, 2 subjects did not meet the ACR criteria for widespread pain and were removed from the survey. Another four questionnaires were incomplete. Thus, 202 completed questionnaires were available for analysis. The demographics of the FM patients and the other three groups are shown in Table ​Table3.3. The groups differed in age, F(3,473) = 492.12 (P < 0.001), with FM patients being 8 years older than healthy controls (P < 0.001). As expected, the four groups differed substantially in regard to pain locations, F(3,473) = 492.12 (P <0.001), with FM patients having many more pain locations than the other three groups (all P < 0.001). The total FIQR scores in the RA (n = 31) and SLE (n = 20) patients were similar and not significantly different (RA: 28 ± 21.0 and SLE: 30 ± 22.5, P = 0.74). Hence, the two groups were merged into a single group (RA/SLE) as the intent was to compare an inflammatory rheumatic disease group with FM. The healthy group had fewer pain locations than the RA/SLE groups (P < 0.001), while the MMD group did not differ from either the healthy controls (P = 0.55) or the RA/SLE (P = 0.29).

Table 3

Demographics of fibromyalgia patients and other groups

In comparison with the fibromyalgia patients: ^aP = 0.25; ^bP = 0.13; ^cP < 0.001. ND, not determined; RA/SLE, rheumatoid arthritis/systemic lupus erythematosus.

The patient FIQR scores, though appearing to be normally distributed, were negatively skewed (Shapiro-Wilk W = 0.978, P = 0.003), slightly favoring the more severe cases (Figure ​(Figure1a).1a). This FIQR distribution was nearly identical to the distribution of FIQ scores (Figure ​(Figure1b),1b), which were also slightly negatively skewed (Shapiro-Wilk W = 0.980, P = 0.006). The mean FIQR total score was 56.6 ± 19.9, with a median score of 58 (95% confidence interval [CI] 53.8, 59.4) (Table ​(Table4).4). The mean FIQ total score was 60.6 ± 17.9, with a median score of 61.9 (95% CI 58.1, 63.0). There were only 12 FM males compared with 190 FM females, and the respective total FIQR scores were 53.2 ± 20.4 and 56.8 ± 20.0 (P = 0.55). Higher scores are indicative of greater dysfunction or symptom severity, and the FIQR sleep quality question had the highest score (7.61 ± 2.4), followed by tenderness to touch (6.86 ± 2.5), energy level (6.80 ± 2.4), stiffness (6.72 ± 2.2), environmental sensitivity (6.19 ± 2.9), and pain (6.01 ± 2.1). As expected, 'difficulty with combing hair' had the lowest score (2.42 ± 2.6), but seven patients had scores of at least 8 on this question. The Cronbach alpha for the FIQR was 0.95, with item-total correlations ranging from 0.56 to 0.93. The item-total correlations for the four new items were 0.69 for memory, 0.56 for tenderness, 0.65 for balance, and 0.57 for sensitivity, strongly justifying their inclusion as part of the FIQR.

Table 4

Revised Fibromyalgia Impact Questionnaire question values in 202 patients with fibromyalgia

CI, confidence interval; FIQR, Revised Fibromyalgia Impact Questionnaire; SD, standard deviation.

Histograms of FIQ and FIQR showing distributions of total scores. (a) The distribution profile of the total Revised Fibromyalgia Impact Questionnaire (FIQR) scores in 202 fibromyalgia (FM) patients. (b) The distribution profile of the total Fibromyalgia Impact Questionnaire (FIQ) scores. There is a slight negative skewness for both distributions. The FIQR Shapiro-Wilk skewness coefficient (W) is 0.978, and the FIQ Shapiro-Wilk skewness coefficient (W) is 0.980.

The goal of giving more weight to function in the FIQR appears to have been successful. Table ​Table55 presents the new weighting for the three FIQR domains contrasted with the original weighting in the FIQ (columns 2 and 4). Columns 3 and 5 present the observed (actual) means for the FIQR and FIQ with the contribution of each domain mean score presented as a percentage of the total scores. As can be seen, the 'imbalance' observed in the FIQ between function and symptom (7% and 74%) has been markedly improved in the FIQR (28% and 53%), approximating the new weighting given to scoring the FIQR (30% and 50%). The contribution of overall impact to total score (19% in FIQ and 19% in FIQR) also approximates the 20% weighting given in each scale. While the new weighting for the FIQR seems to have been successful, there was a significant 3.99-point difference in the total mean scores (P < 0.03). This may be due to the change in weighting reflected by a smaller increase in function scores (+11.31) relative to a greater decrease in symptom scores (-14.85), as shown in column 6, and/or because of other changes and additions to the questions in the FIQR.

Table 5

Comparison of Fibromyalgia Impact Questionnaire and Revised Fibromyalgia Impact Questionnaire weighting on actual and achieved domain scores

This analysis shows that the weighting of the Revised Fibromyalgia Impact Questionnaire (FIQR) closely approximates the given weight. The 'imbalance' observed in the Fibromyalgia Impact Questionnaire (FIQ) between function and symptom (7% and 74%) has been markedly improved in the FIQR (28% and 53%).

Convergent validity was assessed by comparing the FIQR to both the SF-36 and the FIQ. Note that all of the correlations of the FIQ with the SF-36 are negative due to the fact that higher scores on the SF-36 relate to being healthier. The SF-36 subscale scores in the FM patients were physical functioning 39.8 ± 24.4, physical role 13.5 ± 27.1, emotional role 39.1 ± 43.0, vitality 17.6 ± 14.3, emotional health 57.4 ± 20.2, social functioning 43.6 ± 32.5, bodily pain 33.9 ± 18.3, and general health 38.2 ± 21.3. These SF-36 subscale scores were similar to our previous findings [] and a review of the literature [], helping to confirm that the FM population in this study was comparable to most other studies. In general, the three domains of the FIQR and the individual questions correlated most closely with the corresponding subscales on the SF-36 (Table ​(Table6).6). For instance, the FIQR total score correlated best with SF-36 physical functioning and pain subscales (r = -0.71 and -0.69), the FIQR function domain correlated best with SF-36 physical functioning and pain subscales (r = -0.80 and -0.60), the FIQR overall impact domain correlated best with the SF-36 physical functioning and pain subscales (r = -0.60 and -0.64), and the FIQR symptoms domain closely correlated with all of the SF-36 subscales (r = -0.43 to -0.66). When individual questions were looked at, the FIQR pain correlated best with SF-36 pain (r = -0.66), and FIQR anxiety and depression correlated best with the SF-36 mental health subscale (r = -0.72 and -0.63).

Table 6

Pearson correlations of the Revised Fibromyalgia Impact Questionnaire with subscales of the 36-Item Short Form Health Survey

^aThese three correlations under 'emotional role' were not significant. All other correlations were significant: r ≥ 0.15, P < 0.05; r ≥ 0.18, P < 0.01; and r ≥ 0.22, P < 0.001. Note: all correlations are negative as the 36-Item Short Form Health Survey (SF-36) scoring has a direction opposite to that of the Revised Fibromyalgia Impact Questionnaire (FIQR).

As the original FIQ is extensively validated through its use in over 250 studies, we compared FIQR with the original FIQ. The total score of the FIQR in FM patients was 56.58 ± 20 (range 15 to 97), whereas the total score for the FIQ was 60.56 ± 18.0 (range 10 to 96). While this difference is statistically significant (P = 0.03), the strong correlation of 0.88 (P < 0.001) between the FIQR and FIQ indicates that patients' relative standings on the two scales are very similar. This is indicated by the reasonable correspondence between FM participants' scores on the FIQR and FIQ in the scatterplot (Figure ​(Figure2).2). There was a strong correlation of the three domains of the FIQR plus pain with the corresponding domains of the FIQ (Table ​(Table7).7). The correlations along the diagonal (r = 0.69 to 0.88), which represents the relation between corresponding constructs on the new and old scales, are higher than the correlations between different constructs (r = 0.46 to 0.75), those below and above the diagonal. This provides further support for the 'domain' structure of the FIQR.

Table 7

Pearson correlations of major components of the Fibromyalgia Impact Questionnaire with those of the Revised Fibromyalgia Impact Questionnaire

All correlations were significant at P < 0.001. FIQ, Fibromyalgia Impact Questionnaire; FIQR, Revised Fibromyalgia Impact Questionnaire.

A scatterplot of the total score for the Revised Fibromyalgia Impact Questionnaire (FIQR) and the Fibromyalgia Impact Questionnaire (FIQ) on all 202 fibromyalgia subjects (r = 0.88, P < 0.001).

Multiple regression analysis was used to determine how well the three FIQR domain scores predicted the eight SF-36 domains (Table ​(Table8).8). In contrast to the correlational analyses presented in Table ​Table6,6, multiple regression analysis identified both the combined and unique variance that predictor variables contribute to an SF-36 subscale. The three FIQR domains (function, overall impact, and symptoms) were entered simultaneously into the regression equation to predict how much variance in SF-36 domains could be explained by FIQR components. Column 1 shows the multiple R and combined variance. Columns 2, 3, and 4 identify the FIQR components that uniquely predict SF-36 domains. It is seen that all three FIQR domains contributed collectively and uniquely to all SF-36 domains. Column 1 shows multiple correlations ranging from 0.45 to 0.80, with FIQR components collectively explaining 62% of SF-36 physical functioning, 48% of SF-36 pain, and 30% of SF-36 vitality. Columns 2, 3, and 4 show that the FIQR domains predicted unique variance in SF-36 domains, providing good discriminant validity. Overall, FIQR domains predicted unique variance in 15 of 24 instances, providing substantial justification for separating the FIQR into three domains. Notably, FIQR function strongly predicted SF-36 physical functioning and role limitation due to physical health (column 2) whereas FIQR symptoms predicted each of the other six remaining SF-36 domains, including SF-36 pain, vitality, emotional health, well-being, and social functioning (column 4). The FIQR 'overall impact' domain, which assesses whether FM prevented goals from being accomplished and whether the patient felt overwhelmed, predicted SF-36 subscales of pain, role limitations due to physical health, emotional well-being, and social functioning; it did not predict physical functioning, general health, vitality, or role limitation due to emotional health. Importantly, each of the three FIQR domains contributed uniquely to the SF-36 pain subscale, illustrating that each of the FIQR domains is relevant to the assessment of pain in FM. In sum, the FIQR, conceptualized around three linked domains, showed both convergent and discriminant validity in predicting SF-36 subscales.

Table 8

Multiple regression analysis showing how the three domains of the Revised Fibromyalgia Impact Questionnaire predict subscales of the 36-Item Short Form Health Survey

^aP < 0.0001; ^bP < 0.01; ^cP < 0.05; ^dP < 0.001. First column: adjusted R-square (R²) × 100 indicates the total variance in 36-Item Short Form Health Survey (SF-36) subscale accounted for by the common and unique variance in Revised Fibromyalgia Impact Questionnaire (FIQR) function, overall, and symptom domains taken together. Multiple regression (R) indicates the size of correlation between three FIQR domains as predictors taken together with the SF-36 subscale as criterion. Columns 2, 3, and 4 present the standardized regression (β) coefficients, which represent the unique contribution of the predictor variable, and the partial correlation (pr) coefficients, which represent the correlation for the one (FIQR) domain with the SF-36 subscale after controlling for the other two (FIQR) domains.

Discriminant validity was also evaluated by comparing the FIQR total scores in FM patients (56.6 ± 19.9, 95% CI 53.8, 59.4) with the scores in healthy controls (12.1 ± 11.6, 95% CI 10.5, 13.6), patients being treated for RA or SLE (28.6 ± 21.2, 95% CI 22.6, 34.5), and patients under treatment for MDD (17.3 ± 11.8, 95% CI 9.3, 25.2) (Figure ​(Figure3).3). As noted in Materials and methods, the FIQR for these three groups substituted 'health issues' for 'fibromyalgia'. These four total FIQR scores were significantly different: F(3,473) = 247.94 (P < 0.001). The FM FIQR total score was significantly higher than in the three other groups (Tukey HSD test P < 0.001 for all three comparisons). The FIQR in the RA/SLE group (28.6 ± 21.2) was significantly higher than in the healthy group (12.1 ± 11.6) (P < 0.02). The MDD total FIQR score (17.3 ± 12) did not differ from the healthy and RA/SLE groups.

The total Revised Fibromyalgia Impact Questionnaire (FIQR) scores of the 202 fibromyalgia (FM) patients compared with the scores for the 213 healthy controls, 51 patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), and 11 patients with major depression. *Note: a concomitant diagnosis of FM was an exclusion criterion for inclusion of RA/SLE and major depressive disorder (MDD) subjects. SE, standard error.

A similar analysis was conducted to determine whether the FM group differed from the other three groups on the four new FIQR symptoms (memory, tenderness, balance, and sensitivity). If the four new symptoms reflect FM impact, then group differences on these symptoms should emerge, providing evidence for the construct validity for the syndrome. Figure ​Figure4,4, which presents the means of all four groups with respect to each of the four new symptoms, shows that the four groups discriminated between the four subject groups (Wilks lambda = 0.33, RaoR(12, 1,243) = 53.86, P < 0.001), with the FM patients scoring substantially higher than the other three groups. Additionally, the FM group scored substantially higher than all three other groups on all four symptoms (P < 0.001), with the singular exception of the comparison with the MDD group on memory (P < 0.07). Figure ​Figure44 also illustrates the significant mean differences on these four symptoms in the FM group (highest to lowest rankings: tenderness, sensitivity, memory, and balance). Tenderness, the most problematic symptom for FM patients, was significantly higher than both sensitivity (P < 0.004) and memory (P < 0.001). Balance, the least problematic, was significantly lower than both sensitivity (P < 0.001) and memory (P < 0.001). Despite these differences, which contribute to the overall individual differences in the FIQR total scores, the item-FIQR total correlations for the four new symptom items (r = 0.56, 0.57, 0.69, and 0.65) were similar, indicating that they are of nearly equal relevance for defining the FM syndrome. The RA/SLE group had significantly higher scores for the four new symptoms than the healthy controls (P < 0.001), thus justifying the inclusion of RA/SLE as an intermediate group.

A plot of the mean scores for the four new symptoms added to the Revised Fibromyalgia Impact Questionnaire (memory, tenderness, balance, and environmental sensitivity) against each of the four groups: fibromyalgia (FM), rheumatoid arthritis/systemic lupus erythematosus (RA/SLE), healthy, and major depressive disorder (MDD).

Discussion

We describe and validate a revised version of the FIQ: the FIQR. This version was developed in an attempt to correct some of the problems in the wording, omissions, concepts, and scoring of the original FIQ [,]. There are several modifications of the FIQ which have been incorporated into the FIQR, while retaining the basic domain structure in terms of function, overall impact, and severity of symptoms that are characteristic of FM (Table ​(Table1).1). Each of the three FIQR domains was highly correlated with the total FIQR score and predicted unique variance in SF-36 domains, providing good evidence for discriminant validity. The mean total score of the FIQR was approximately 4 points lower than the mean FIQ total score; we attribute this to the change of the weighting in the scoring algorithm.

The first domain, function, in the FIQR has been reduced to 9 questions from the original 11 questions and now has a weighting of 30% of the total score, as opposed to 10% in the FIQ, to reflect the relative importance of function in assessing the impact of FM. The specific questions in the function domain have been modified to reflect a better balance between large-muscle activities of the upper and lower limbs and have less gender and ethnicity bias than the FIQ. Importantly, the FIQR function domain was most highly correlated with the SF-36 physical functioning subscale. In a multiple regression model, FIQR function most strongly and uniquely (that is, after removing shared and unique variance with the other domains) related to SF-36 physical functioning (Table ​(Table88).

The second domain, overall impact, has been completely revised to reflect two subdomains, namely the overall impact of FM on functional ability and the overall impact of FM on the perception of reduced function (Figure ​(Figure1).1). The FIQR overall impact domain was most highly correlated with the SF-36 subscales of physical functioning and pain (Table ​(Table6).6). In a multiple regression analysis, the overall impact domain was most specifically associated with the SF-36 subscales of social functioning, role limitation due to physical health, and emotional well-being. There was a moderately good correlation of the FIQR overall impact domain with the FIQ overall (Table ​(Table8).8). The weighting of this FIQR domain remains the same as the FIQ (that is, 20% of the total score).

The third domain, symptoms, retains the original questions in the FIQ regarding pain, stiffness, lack of restorative sleep, poor energy, anxiety, and depression and adds four additional questions relating to tenderness, memory, balance, and environmental sensitivity (Figure ​(Figure1).1). These questions were added in light of ongoing experience with OMERACT patient delphi exercises [], ICF guidelines [8], patient surveys [], and clinical testing []. The weighting for this FIQR domain is 50% of the total score as opposed to 70% in the FIQ. These four new symptom questions all had strong correlations with the total FIQR score, and each provided discriminant validity between the healthy controls, the patients with RA/SLE, and the patients with MDD. Furthermore, all four items discriminated between the four subject groups, with the FM patients scoring substantially and significantly higher than the other three groups. The scores on memory were similar in the FM group and the MDD group, probably an expression of the well-documented memory problems associated with depressive illness [,]. It is interesting to note that, although the FM and MDD groups had similar scores on depression and anxiety, the FM patients had distinctively higher scores on tenderness, environmental sensitivity, and balance. This was also the case when comparing the FM with the RA/SLE group. Thus, the FM patients displayed distinctive responses to these four new questions.

Although all of the FIQR symptom items and the FIQR symptom domain were correlated with all of the SF-36 subscales, multiple regression analysis indicated that the symptom domain provided more unique variance to six of the SF-36 subscales (role limitation due to emotional health, vitality, emotional well-being, social functioning, pain, and general health) than did the other two FIQR domains. Coupled with the function domain uniquely predicting SF-36 physical functioning, this analysis provides substantial discriminant validity for the domain structure of the FIQR in relation to the SF-36. Each of the 21 FIQR questions can be related to relevant outcomes as specified by the ICF guidelines [] (Table ​(Table9).9). Prodinger and colleagues [] reported a closer ICF correspondence between the FIQ and SF-36 compared with 14 other general health instruments; thus, the current finding showing a strong relation between FIQR and the SF-36 provides further confirmation of the content validity of the FIQR. However, it is worth noting that substantial FM variance (column 1 of Table ​Table8)8) is not captured by the SF-36, suggesting that the FIQR is measuring unique variance that is distinctive and specific to the FM syndrome.

Table 9

Guidelines of the International Classification of Functioning, Disability, and Health applied to each of the 21 questions of the Revised Fibromyalgia Impact Questionnaire

FIQR, Revised Fibromyalgia Impact Questionnaire; ICF, International Classification of Functioning, Disability, and Health.

The use of a numeric rating scale using 11 boxes, scored 0 to 10, in the FIQR as opposed to the combination of Likert and VAS scaling in the FIQ did not result in significant differences in the total scores in the focus group analysis (Table ​(Table2).2). Furthermore, there was excellent correlation between the paper version with VAS scoring (FIQ-P VAS), the paper version using the 0-to-10 numeric rating (FIQ-P), and the online FIQR using the 0-to-10 numeric rating (FIQR-OL) (Table ​(Table2).2). The use of the numeric rating considerably simplifies the scoring algorithm for the FIQR and obviates the need to use a ruler to measure VAS scores. Furthermore, the use of the numeric rating scoring greatly simplifies the conversion of a paper version of the FIQR to an online version, as done in this study. The paper version of the FIQR took approximately half the time to complete compared with the FIQ. On the other hand, the SF-36 took nearly four times as long to complete as the FIQR. Our favorable experience with the use of a numeric rating scale compared with continuous VAS scoring reflects the experience of several other groups [-] and is in line with the recommendations of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) []. This simplification and greater efficiency should make the FIQR easier to use by researchers and physicians. The FIQR shows good ability to discriminate between FM patients and patients with RA, SLE, and MDD who do not have concomitant FM.

There are several limitations to the interpretation of this study. The testing was done entirely online; thus, it is not possible to equate these results with a paper version of the FIQR. However, a comparison of the paper and online versions was completed by the focus group and showed no significant differences between the two methods. No test-retest reliability was performed on the online participants, but again the limited information from the focus group suggested good test-retest reliability. Only 12 males completed the questionnaires; thus, their FIQR scores cannot be considered representative of a large male population. We were able to recruit only 11 subjects with MDD who did not have FM; thus, the validity of comparisons associated with MDD may be limited. We could not estimate the sensitivity to change of the FIQR or the minimal clinical important difference (MCID) for scoring the FIQR, as has been done for the FIQ []; these analyses will have to await the use of the FIQR in a large clinical trial. Given that there are currently no generally accepted objective measures of FM severity, validated questionnaires measuring patients' subjective responses will continue to be important. In this respect, we hope this revised version of the FIQ will be useful to both researchers and clinicians.

Conclusions

A revised version of the FIQ, called the FIQR, is described herein. The FIQR has sound psychometric properties, discriminates between FM patients and patients with RA, SLE, and MDD, takes just over 1 minute to complete, is easy to score, and can be used in online surveys. The FIQR has a good correlation with the original FIQ, thus providing the ability to compare the results of studies using the older version with studies using the revised version.

Abbreviations

Fm 2009 Portuguese Ltc Properties Online

ACR: American College of Rheumatology; ANOVA: analysis of variance; CI: confidence interval; FIQ: Fibromyalgia Impact Questionnaire; FIQ-OL: an online version of the Fibromyalgia Impact Questionnaire; FIQ-P: the original paper version of the Fibromyalgia Impact Questionnaire; FIQR: Revised Fibromyalgia Impact Questionnaire; FIQR-OL: an online version of the Revised Fibromyalgia Impact Questionnaire; FIQR-P: a paper version of the Revised Fibromyalgia Impact Questionnaire using 11 boxes scaled 0 to 10; FIQR-P VAS: a paper version of the Revised Fibromyalgia Impact Questionnaire using a 100-mm visual analog scale scoring instead of 11 boxes; FM: fibromyalgia; HSD: honestly significantly differences; ICF: International Classification of Functioning, Disability, and Health; MDD: major depressive disorder; OMERACT: Outcome Measures in Rheumatology; RA: rheumatoid arthritis; SF-36: 36-Item Short Form Health Survey; SLE: systemic lupus erythematosus; VAS: visual analog scale.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

RMB conceived of and guided the study, directed the focus group, provided the algorithms for Survey Monkey, downloaded and analyzed the results, and drafted the manuscript. RF provided statistical analyses and was involved in the writing and editing of the manuscript. KDJ assisted in the focus group and was involved in the writing and editing of the manuscript. RW assisted in the focus group and was responsible for checking the integrity of the databases. BKH recruited the patients with RA from his clinical practice and reviewed the manuscript. RLR recruited the patients with MDD from her clinical practice and helped in editing the manuscript. All authors read and approved the final manuscript.

Fm 2009 Portuguese Ltc Properties Inc

Supplementary Material

A PDF that provides the 2 page version of the FIQR that is suitable for printing.

A PDF that provides the 2 page version of the FIQR that was used in the non-fibromyalgia patients; this questionnaire does not use the word 'fibromyalgia' and is termed the Symptom Impact Questionnaire (SIQR).

Acknowledgements

The authors thank Jessica Morea Irvine, Jillian F Bain, and Janice Hoffman for their work in subject recruitment and maintaining our database of FM patients. This work was supported by the Fibromyalgia Information Foundation.

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