Recently, molecular and genomic approaches have been con- sidered important tools to shed light on the complex physiologi- cal and metabolic pathways leading to flowering.

In recent years, numerous flowering-gene promoters and inhibitors have been identified, isolated and characterized.

Extensive research has been done in A. thaliana, for which the balance between promo- ters and inhibitors is decisive for the adequate determination of flowering time and floral identity (Chon and Yang, 1999; Kobayashi et al., 1999).

However, in woody tree species, little has been done on this subject.

The results presented herein regarding the expression of flowering genes affected by fruit load offer an insight into the molecular mechanisms underlying alternate bearing in citrus trees.


In several species, flowering ability has been demonstrated to be influenced by the integration of environmental signals from the photoperiod and vernalization pathways (Onouchi et al., 2000; Amasino, 2005; Sheldon et al., 2009), mainly modulated by two floral integrators, the FT and the SOC1 genes (Kardailsky et al., 1999; Borner et al., 2000; Lee et al., 2000; Samach et al., 2000).

Both genes have been described as floral promoters and their overexpression induces early-flowering phenotypes (Lee et al., 2006; Sreekantan and Thomas, 2006; Zhang et al., 2010).

The FT gene has been demonstrated to be a pivotal factor controlling flowering period in numerous species (Faure et al., 2007; Chab et al., 2008; Hisamoto et al., 2008; Zhang et al., 2010).

The present results support this hypothesis and further relate it to the effects of fruit load in citrus trees just as autumn/winter temperature enhances its expression (Nishikawa et al., 2007).


Leaves from off trees (high-return bloom-flowering in spring) showed significantly increased mRNA transcript levels as compared with those from on trees (low return bloom).

Thus, whereas on trees showed stationary basal levels of expression, a progressive increase in CiFT levels was observed in leaves from off trees (Fig. 4) until December, concomitantly with a higher flowering rate the following spring (Fig. 2).


These results demonstrate, on the one hand, that an increased FT protein constitutes a signal per se that exports from leaf to the shoot apical meris- tem, where floral differentiation takes place (Notaguchi et al., 2008) and, on the other, that a translated FT protein can be translocated to the floral meristem at any time (Lin et al., 2007; Turck et al., 2008).

Nevertheless, the translocation pathway followed by FT protein into the apex remains unknown.


Although not always significant, SOC1 also showed higher expression levels in leaves from off trees compared with those registered for on trees, particularly during the floral induction period (Fig. 5).

Lee and Lee (2010) reported that constitutive expression of SOC1 promotes early flowering, while recessive loss-of-function seems to delay flowering (Onouchi et al., 2000).

Although isolated in only a few plant species, highly conserved homologues of this gene have been identified in numerous species, including citrus, in which the constitutive expression of several SOC1-like homol- ogues induces early flowering and delays senescence of floral organs (Tan and Swain, 2007).

In this sense, the present results confirm the role of this gene in flowering resulting from alternate-bearing adult trees.


Unlike the functions attributed to SOC1 and FT genes, FLC has been described to encode a MADS-domain protein able to repress flowering (Michaels and Amasino, 1999).

The present data showed no differences in FLC activity between on and off trees until December (Fig. 6).

From this time onwards, there was a progressive increase in transcript levels in leaves from on trees, whereas those from off trees showed no change or even a slight decrease.


Some authors have pointed out that ver- nalization promotes flowering through a permanent epigenetic repression of FLC (Michaels and Amasino, 1999), probably through histone methylation and changes in chromatin confor- mation (Bastow et al., 2004; Sung and Amasino, 2004).

In the present study, trees with increased amounts of FLC mRNA transcripts near spring corresponded to on trees that did not flower.

Additionally, previous reports have indicated antagon- istic effects of flowering promoters and FLC on the expression of target genes leading to flowering.


The study of regulatory pathways demonstrates that this gene is located upstream along the major pathways, since FT overexpression does not appear to affect FLC expression (Moon et al., 2005; Lee and Lee, 2010).

Likewise, it has been proposed that elevated levels of FLC expression may be responsible for reductions in FT activity (Michaels et al., 2005).

In this context, the marked increase in FLC measured in the on trees from December onwards (Fig. 6) might be related to the suppression Muñoz-Fambuena et al. - Fruit regulation of flowering gene expression in citrus 516 of CiFT activity in their leaves compared with off trees (Fig. 4) and, therefore, with the inhibition of flowering.


Moreover, the results show that SOC1 expression increased in off trees before the sharp increase in CiFT, so the activation pathways appear to work, at least partially, autonomously; fur- thermore, from November onwards, SOC1 expression did not parallel the increased CiFT gene expression.

This is not unusual since, at least partially, self-determining regulatory mechanisms for FT and SOC1 activity have been reported recently (Lee and Lee, 2010).

Therefore, this hypothesis can be extrapolated to the molecular mechanisms affecting flower- ing through effects of fruit load.

Moreover, whereas CiFT expression was significantly higher in off trees as compared with on trees until the end of February, significant differences in SOC1 expression disappeared by the beginning of January.


Although TFL1 has been described as a crucial floral timing regulator in several species (Shannon and Meeks-Wagner, 1991; Liljegren et al., 1999), in the present study no differ- ences in CsTFL expression dependent on fruit load were found (Fig. 7).

This gene was identified and isolated in Citrus sinensis (Pillitteri et al., 2004a) and has been proposed to participate in the development and maintenance of vegeta- tive growth, repressing flowering in several plant species (Esumi et al., 2010; Mohamed et al., 2010).

In addition Nishikawa et al. ( 2009) have reported no variations in the expression of this gene during induction and flower bud devel- opment, neither in trifoliate and deciduous Citrus-like species (P. trifoliata) nor in Satsuma mandarin (C. unshiu), indicating that this gene is related to juvenility processes rather than to annual floral transition.


Since there were no differences between on and off trees regarding CsTFL expression, differ- ences in flowering as a consequence of fruit load do not appear to be dependent on this gene.


Finally, AP1 and LFY genes have been reported to promote flowering in diverse species including citrus, although their primary role appears to be linked to the determination of floral identity (Pillitteri et al., 2004b).

Although transgenic approaches have demonstrated that both genes strongly interact with other physiological processes, such as competition for nutrients, their constitutive expression per se reduces the juve- nility period in transgenic citrus (Peña et al., 2001; Duan et al., 2010).

In particular, AP1 seems to be more effective and dynamic than LFY in the induction of flowering (Peña et al., 2001), orchestrating floral initiation by repressing the action of inhibitors at the level of the meristem as stated by Kaufmann et al. ( 2010).


The present results showed a reduced expression of CsAP1 in leaves in response to the pres- ence of fruit (Fig. 8).

Differences between the levels of expression in leaves from on and off trees were significant during the whole study period despite the reduction in these levels from January onwards.


It is noteworthy that LFY activity has been associated with the control of floral meristem identity in Arabidopsis (Weigel et al., 1992).

Moreover, recent studies on fruit trees, including citrus, demonstrated that once floral identity is determined, high LFY expression levels are almost limited to reproductive organs (Pillitteri et al., 2004b).

This observation might also be linked to the absence of differences in CsLFY expression in leaves from on and off trees between September and January.


The significantly higher values found in off trees at the end of February support the main role of this gene on bud differentiation and/or floral identity rather than on inductive processes.


In conclusion, in Citrus fruit load inhibits flowering by repressing CiFT and SOC1 expression in leaves during the floral bud induction period, whereas CsTFL and FLC expression does not seem to be associated with fruit load.

Fruit load reduces CsAP1 gene expression in leaves during the floral bud induction period, although differences between on and off trees were attenuated from January onwards, indicat- ing the onset of floral differentiation.

This hypothesis is also reinforced by the significant increase in CsLFY expression found in leaves from off trees only in late February.

The FLC-increased expression in on trees from early winter onwards might well be related to the suppression of CiFT expression in their leaves and, therefore, with inhibition of flowering.


Studying a process in a new species often relies on focusing our attention to a candidate gene, encoding a protein similar to one with a known function.

Not all the choices seem to be prudent.

This Viewpoint includes an overview of issues that are encountered during research of candidate genes.

Defining a match for a gene of interest, deciding whether variation in ESTs or RNAseq data for a certain transcript, represent more than one gene.

The problem of incorrect annotation of genes due to incorrect in-silico splicing, is also mentioned.

The author’s humble opinion on how to deal with these issues is provided.

The vast amount of new sequence data provides us with great possibilities for giant leaps in our understanding.

Still, we cannot afford to skip over the tedious steps required to confirm that we are indeed studying the correct gene, and try to be sure that the complex expression pattern we observe is not a composite of several genes.


One rationale behind studying ‘model’ plants (MPS) such as arabidopsis is that different plant species are likely to use conserved mechanisms to control development, metabolism and other processes.

By learning from one species that is easy to study, we might extrapolate these findings to different, more complex species, which are either more important to agriculture, or simply our ‘favourite’ species (OFS).

For example, while flowering of different plant species is mediated by different internal and external cues, it seems to be triggered by a common protein, FLOWERING LOCUS T (FT), which functions as a universal ‘florigen’ [1].

The MADS box proteins that confer organ identity in flowers (termed the ABC model) are another example of conserved function [2].

It is obvious that not everything will be the same among species, and the differences help explain why flowering plants are so diversified.

Once we decide to study a certain event in OFS, we might begin by presuming nothing and start our studies with a clean slate.

Many choose to also use a parallel approach in which they study ‘candidate’ genes that encode proteins that were functionally characterized in MPS.

This Viewpoint discusses problems that might rise in the course of picking such candidate genes.


If X and Y are identical twin dogs and someone scanned all dogs on the planet for the one that is most similar (in genome sequence) to X, they should end up with Y. If X was in a room with one more dog (Z) and several humans, a scan limited to the room would probably identify Z as most similar to X. The depth of the search clearly depends on the available dataset.

If I want to identify, in OFS, a gene encoding a protein most similar in sequence to protein X from MPS, I would need to have access to the full genome of OFS, to identify the best match.

Still, I might be lucky and identify a gene encoding a protein orthologous to X from a small dataset.

When can I assume that the gene I identified indeed encodes a protein that has a similar role to the one described for protein X in MPS?

There is no straightforward answer to this question and there are different points of view regarding how rigorous the analysis should be before making such a statement.

If XMPS and XOFS share extended homology, and mutations in each of the genes cause similar phenotypes, one might assume that these are orthologous genes which have originated from the same gene in their common ancestor and share the same function.

Reaching this result would depend on how easy it is to obtain loss of function mutations in both species, and whether or not there are redundant genes that might mask the phenotype of loss of function.

In many species the genome has gone through duplications or has become polyploid.

Thus, reaching a loss of function phenotype becomes even more difficult.

Without loss of function phenotypes, similar expression profiles can also strengthen a choice of an orthologue among paralogues [3].

Clearly, homology within functional domains is a better indicator than overall similarity, since a loss of an active site would make a paralogue into a pseudogene [4].


In a recent paper, we described for the first time the effects of fruit on the expression of putative homologues of genes involved in flowering pathways.

It was our aim to provide insight into the molecular mechanisms underlying alternate bearing in citrus.

However, a bioinformatics-based critique of our and other related papers has been given by Samach in the preceding Viewpoint article in this issue of Annals of Botany.

The use of certain bioinformatic tools in a context of structural rather than functional genomics can cast doubts about the veracity of a large amount of data published in recent years.

In this response, the contentions raised by Samach are analysed, and rebuttals of his criticisms are presented.


Alternate bearing is a result of complex metabolic and molecular regulatory pathways in which flowering-related genes are strongly implicated.

In a recent paper published in this journal we reported, for the first time, the effects of fruit on the expression of putative homologues of genes involved in flowering pathways.

It was our aim to provide insight into the molecular mechanisms underlying alternate bearing in citrus (Citrus clementina) due to crop load.

For detailed information, please refer to our original paper [1].


The main conclusion derived from our study was that fruit modulates seasonal expression of flowering genes in alternate-bearing ‘Moncada’ mandarin: novel and original research in the context of fruit crop physiology (indeed, the publication was awarded a Graduate Prize by the journal).

The study of the expression pattern of flowering-genes of on (fully loaded) and off (without fruit) trees revealed that mainly CiFT and also floral-identity genes (CsAP1 and CsLFY) are highly involved in the process.

No reference to choosing any new developmental regulator, as Samach [7] generalizes, was included in our manuscript.


Moreover, he claims that ‘the vast amount of new sequence data provides us with great possibilities for giant leaps in our understanding’, and he globally criticizes some current, frequently used methodological approaches.

It is certainly the case that in recent decades an astonishing advance in the development of new databases and bioinformatic tools and platforms has taken place [5].

Nevertheless, current genome programs generate large amounts of data that require significant processing, storage and delivery to the research community [8], not always resulting in a precise or complete annotation of genes and associated proteins – especially so if referred to EST collections.


Previous publications have already warned about the current limitations of bioinformatics [6] and in this context it is well known that, as the volume of sequence data increases exponentially, the number of genes of unknown function – and, therefore, the large amount of associated uncertainties, gaps or mismatches – does as well [4].

It is fairly easy to understand how this excess of information may be conveniently interpreted when introduced into functional research, and likewise conclusions may be exaggerated in scenarios of in silico gene prospecting.


In our opinion, however, this potential lack of precision and the continuous improvement of bioinformatic procedures should not be exploited to spread doubts about the conclusions of functional studies that are just focused on the role of previously described genes.


In his Viewpoint article, Samach alerts the reader to the problems that arise when mixing new databases with old ones and their corresponding notations.

In the following paragraphs we will give concise evidence as to why the conclusions we presented previously are as precise as possible in terms of functionality, the main goal of our research.


(1) To analyse the expression of those genes previously identified and sequenced in citrus based on an EST collection, the primers we used were selected for the specific amplification of the targets according to the current literature and the corresponding public annotation.

Any new developmental regulator was studied.

Just as an example to illustrate that Samach’s assertions are not necessarily as precise as stated, we point out that when you BLAST the EST supposedly containing CiFT to public databases (i.e. NCBI) the unequivocal output is, precisely, CiFT.

In addition, it is worth mentioning that in combining in silico the old with new and other particular non-published databases, Samach appears to ignore that the increase in the number of genes of a given family is not a reason to invalidate the functionality of a target, previously-annotated gene.


(2) To analyse the expression of those genes not yet identified or annotated, a consensus sequence formed by all EST homologues (from the Citrus Functional Genomics Project; http://bioinfo.ibmcp.upv.es/genomics/cfgpDB/) to the target Arabidopsis gene was built [2], and a specific primer was designed for amplification.

This methodology (with its understandable limitations) is not new and in fact it is widely represented in the bibliography.


(3) In order to provide transparent information for the reader, we decided to include in our study, together with the sequence of the primer, a table with details about the notation of the EST with highest similitude to the target gene previously described (see point 1) or the consensus sequence designed (point 2).

The fact that this sequence was or was not annotated in the referenced database is not so relevant from a functional perspective.


(4) Finally, the use of sequences from new, published databases (e.g. Aleza et al., 2009) instead of being from previous ones would only affect the nomenclature and codes in our published table.


All things considered, we understand that the ultimate goal of functional genomics is to integrate large amounts of data so as to increase basic knowledge about key biological processes.

Our study into the molecular mechanisms underlying alternate bearing in fruit trees is a good example – with the known limitations in the use of EST collections.

And we hope that further studies supported with new data will confirm or improve our published results – which is, after all, the ultimate goal of scientific research.


Diagnosing the SI joint as the primary or sole pain generator (PG) can be complex as patients often present with a combination of low back, groin, gluteal, and/or leg pain and the symptom profile may mimic other disorders of the lumbar spine and hip [2, 9].

Additionally, some patients present with more than one pain generator within the lumbar spine-SI joint-hip axis, making the identification of the primary versus secondary pain generators more challenging [3].

Furthermore, SI joint imaging studies are typically neither sensitive nor specific to abnormalities in the absence of trauma, tumor, ankylosing spondylitis, or infection [10].


SI joint pain can be debilitating and treatment with non- operative care is often unsuccessful.

The impact of pain on persons living with the disease is similar to that associated with other prominent orthopedic conditions routinely treated surgically [11].

Furthermore, the economic burden of non- operative care is significant for Medicare as well as commercial payer entities with a 5-year estimated cost of $270 million for Medicare beneficiaries and a 3-year estimated cost of $1.6 billion per 100,000 commercial covered lives [12, 13].


Surgical treatment options for SI joint disorders have been unattractive until relatively recently.

Open arthrodesis, commonly performed throughout the 1900s, is now reserved primarily for traumatic pelvic ring fractures due to the invasiveness of the procedure, coupled with a high morbidity rate [14-16].

In recent years, several minimally invasive Rudolf and Capobianco techniques for fusing the SI joint have been introduced into the surgical repertoire [17-21].

MIS SI joint fusion for certain SI joint disorders (degenerative sacroiliitis and SI joint disruptions), specifically using a series of triangular titanium implants, has been shown to result in lower morbidity, including shorter operating times and hospital stays, fewer complications, a lower reoperation rate, and higher gains in patient quality of life compared to the open surgical method, as evidenced by a recent comparative cohort study [22].


The current body of medical literature substantiates positive short to mid-term clinical outcomes [17, 23-25].

However, no long-term clinical or radiographic outcomes have been published to date.

Herein we report 5-year clinical effectiveness, safety and radiographic outcomes in patients treated with MIS SI joint fusion for degenerative sacroiliitis or sacroiliac joint disruptions using a series of triangular, porous titanium plasma spray (TPS) coated implants (iFuse Implant System ® , SI-BONE, Inc., San Jose, CA) from a single center.


All consecutive patients who underwent MIS SI joint fusion between October 2007 and March 2009 at a single center were identified.

Prior to surgery, all patients were diagnosed with either degenerative sacroiliitis and/or SI joint disruptions using a detailed history, combination of physical provocative maneuvers specific to the SI joint, image-guided intra-articular SI joint injections and various imaging modalities [17].

MIS SI joint fusion was performed in all patients by placing a series of implants laterally across the SI joint, as previously described [17, 23].

Patients were contacted and asked to participate in a long-term evaluation, which included a clinical exam as well as an optional radiographic imaging component.

Patients signed a study- specific, IRB-approved consent form before beginning any study-related activity.


Patients were asked to reveal and discuss any further surgical treatment they received for SI joint, lumbar spine, pelvic or hip disorders.

A series of patient reported outcome instruments, described below, was also administered.

Participants who resided outside of a reasonable travel distance were given the opportunity to provide responses by phone or mail.

Patients who consented to the radiographic component of the study had both plain film radiographs (outlet and anteroposterior (AP) views) and computed tomography (CT) scans of the pelvis.

These imaging tests were used to assess implant position, evidence of lucency adjacent to the implant, qualitative increase in bone density adjacent to the implant, and presence of intra-articular osseous bridging.

The 5-year images were compared to those previously acquired closest to the one-year follow-up interval.


Data extracted from the medical charts included demo- graphics, diagnosed pain generators in the lumbar spine-SI joint-hip axis, pain treatments received, perioperative measures, adverse events, one-year imaging studies, and previously administered patient reported outcomes at 12- and 24-months postoperatively, described below.


Pain and functional outcomes were assessed in a prospective manner pre-operatively and at 12-, 24- and 60-months postoperatively.

Level of pain was assessed using a 0-10 visual analog scale (VAS).


Prior to the initial experience with the surgical procedure, a 9-question SI joint- related health outcomes survey was created with response domains taken from both the SF-36 and Oswestry Disability Index (ODI) (Fig. 1): pain level, the ability to perform light, moderate and vigorous activities, quality of sleep, lifting ability, happiness, social activities, and the effect of pain on social life [17].

A numerical rating scale of 0-10 with 0 representing no pain or difficulty and 10 representing the worst pain imaginable or severe difficulty was used for all domains.


Satisfaction with surgery was assessed in a binary fashion (yes or no) by asking if the patient would have the same surgery again for the same result.

The SI joint-related health outcomes survey and VAS were administered preoperatively and at 12- and 60-months postoperatively.


At 24 months, patients were contacted to assess SI joint pain on VAS.

The ODI was administered at the 60-month visit only.

Satisfaction and safety events were collected at all postoperative time points.


Demographic variables were tabulated and expressed as frequency and means with standard deviation, where appropriate.

A repeated measures analysis of variance (ANOVA) was used to compare VAS pain scores from baseline to all postoperative time points.

A paired t-test was used to assess improvement from baseline to the 60-month time point on the SI joint survey.

An unpaired t-test was performed to assess the effect of sex and history of prior lumbar spinal fusion on outcomes.

Statistical analyses were performed using R software [26].

Clinical improvement was defined using previously validated minimum clinically important difference (MCID) and substantial clinical benefit (SCB) values for back pain on VAS.

MCID is defined as a change of >2.0 points and SCB is defined as a 2.5-point decrease or a raw score of < 3.5 [27, 28].


Institutional Review Board approval was obtained before beginning this study.


1. How much pain are you in at this time?


2. How well are you able to perform light activities like walking a block or dressing yourself?


3. How well are you able to perform moderate activities like playing golf, walking half a mile, or dancing?


4. How well are you able to perform vigorous activities like running or moving furniture?


5. How much is your sleep disturbed by pain at this time?


6. How well are you able to lift items off the floor at this time?


7. How would you assess your level of happiness at this time?


8. How interested are you in socializing at this time?


9. Because of pain, how much is your socializing limited at this time?


Of 21 consecutive patients who underwent MIS SI joint fusion, 17 were available for follow-up and form the analysis cohort.

Of those not available, 2 had died unrelated to spine conditions, one was lost to follow-up and one suffered a severe neck trauma rendering the patient quadriplegic and unable to provide relevant data.

All available patients participated inthe clinical portion of the study and 15 of 17 (88%) agreed to participate in the radiographic component.


Mean subject age was 58 (±14) years (range 36-85), 77% were female and 47% had undergone lumbar spinal fusion prior to SI joint fusion (Table 1).

Slightly more subjects had the right SI joint treated (53%) compared to the left (41%), and one patient underwent bilateral treatment.

Mean operating time was 65 (±18) minutes, range (43-110).

There were no intraoperative complications.

Postoperative events, which primarily included hematoma (1), cellulitis (2), and deep infection secondary to diverticulitis (1), were previously reported in detail [17].


Improvement in pain was clinically and statistically significant at all follow-up intervals compared to baseline (all p<0.001) (Table 2).

All subjects who reached MCID also reached SCB.

The percentage of patients who achieved both MCID and SCB remained high at each time point (77%, 82%, and 88% at 12-, 24- and 60-month visits, respectively).

No statistical effect was found for sex, or history of lumbar fusion on pain improvement at any time point.

At 60-months, statistically significant improvement was seen in 6 of 8 domains of the SI joint survey instrument (Table 3): the ability to perform light, moderate and vigorous activities, sleep disturbance caused by pain, overall happiness, and the effect of pain on social life.

The ability to perform light, moderate and vigorous activities showed continual improvement from 12 months to the 5-year time interval.


Patient satisfaction scores obtained at the 12-month interval were unchanged at 2- and 5-years postoperatively; 82% (14/17) would have the same surgery again for the same result at all time points.


ODI scores were obtained at the 5-year follow-up only (Table 4).

Mean (SD) ODI score was 21.5 (22.7).

Fairbank categorized scores in terms of degree of disability, with 0-20 representing minimal disability and 21-40 representing moderate disability requiring conservative care only [29].

Results show the majority (71%) of subjects are living with minimal or moderate disability.


Pelvic AP and outlet view plain films radiographs and a pelvic computed tomography (CT) scan were performed on 15 subjects; 45 implants were assessed.

Imaging studies obtained at 5 years were compared to available studies acquired as close as possible to the one-year postoperative time point.


A qualitative comparison of 1- and 5-year pelvic plain film radiographs, including AP and outlet views, revealed no change in implant position (Fig. 2).

CT scans of the pelvis with axial, sagittal, and coronal reconstructions documented increased bone density circumferentially along three implant walls for all implants on both the iliac and sacral segments.

Evidence of osseous bridging across the SI joint was clearly seen on 13 of 15 (87%) of patients (Fig. 3).


On x-ray, what appeared to be full-length lucency (absence of bone adjacent to an implant) along the wall of the implant was consistently observed on at least one implant in all patients on AP view.

However, this observation was not evident on the outlet view.

Upon review of CT imaging, this apparent lucency was confirmed to be an artifact (Fig. 4).


Assessment and comparison of CT scans at 1- and 5-years revealed a consistent pattern of artifacts at the corners and periodically along the wall of an implant, which were non-progressive and unchanged in equivalent projections on the axial, sagittal and coronal sections.

A small area of true focal lucency was observed on CT scans in 4 patients; along the superior edge of the most cranial implant on the iliac side in 3 patients, and on the superior edge of the most caudal implant on the iliac side in one patient (Fig. 5).

Other findings included a regular pattern of sclerotic bone response at the implant entry point in the ilium, on primarily the superior implant (Fig. 6).

A detailed explanation of the physics of CT imaging of triangular titanium implants is outside the scope of this manuscript and will be reported separately.


Three subjects in the current cohort did not improve satisfactorily.

To understand why these patients failed to improve and to refine patient selection criteria for MIS SI joint fusion, an in-depth interview was performed for each patient.

Patient vignettes are described below.


Subject 1012 is a 72-year old woman who presented to the clinic complaining of low back and pelvic pain.

The subject's history included a successful total knee replacement as well as L3-L5 arthrodesis for degenerative thoracolumbar scoliosis, symptomatic spondylosis and spondylolisthesis.

At baseline, the lumbar spine and SI joint were confirmed as pain generators using physical and clinical exam, imaging studies, and injections as appropriate.

Non-operative management was employed for lumbar spinal pain.

Based on the pain improvement associated with image- guided intra-articular SI joint injection, MIS SI joint fusion was performed without postoperative complications.

After surgery, she continued to have persistent back pain and buttock pain with walking.

Subsequent imaging studies revealed a progression of her scoliotic curve above L3 with pelvic obliquity and clinical exam suggested multiple pain generators including thoracolumbar spine and degenerative joint disease of the hip.


Pelvic and spinal radiographs at the 5-year visit, and comparison to imaging at 1-year, revealed her SI implants to be intact with no signs of loosening, and a progression of spondylosis at levels above L3.

The 5-year pelvic CT scan showed increased bone density along the walls of the implants, suggestive of biological fixation of the implants in bone.

There were no imaging findings to suggest implant failure as explanation for the subject's residual pain.


In addition to her SI joint problems, this patient suffers from multiple pain generators including hip dysfunction secondary to pelvic obliquity and spondylosis associated with degenerative scoliosis.

A review of this case provokes concern that the symptomatology of other pain generators may have overshadowed any potential improvement after SI joint treatment.

Results from a single image guided intra- articular SI joint injection may be vulnerable to misinterpretation in the context of multiple pain generators.

Some patients may benefit from a second injection.

Positive results on the second injection will confirm the SI joint as the primary PG.

However, an equivocal response of less than 75% pain reduction would suggest the SI joint as a secondary PG [30].

No pain improvement rules out the SI and indicates that other PGs in the lumbar spine-SI joint-hip axis need further investigation.


Subject 1013 is a 50-year old female who presented to the clinic post L4-S1 arthrodesis with complex pain syndrome and concomitant chronic conditions requiring multiple medications to manage her pain.

Furthermore, due to her diminished ambulatory capability, she required assistance in performing activities of daily living.

Subject symptoms and findings on physical exam suggested degenerative sacroiliitis.

The SI joint as a pain generator was confirmed by intra-articular SI joint injection.

The subject underwent a single-side SI joint fusion.


She experienced good pain improvement on the operative side, prompting her to undergo diagnostic testing on the contralateral side followed by SI joint fusion.

Postoperatively, she experienced significant improvement in ambulation and capacity for activities of daily living and near complete resolution of her bilateral SI joint pain.

One year later, her degenerative hip joint disease had progressed, resulting in a left-sided total hip replacement.

This subject declined to participate in the imaging component of the study.

The degradation of function and high ODI score at the 5-year assessment seems associated with recurrent spine-related low back pain.


Subject 1002 is a 50-year old female who underwent left SI joint fusion for degenerative sacroiliitis after previous L4- S1 instrumented arthrodesis for degenerative spondylosis and spondylolisthesis.

Postoperatively, she suffered from an infected hematoma secondary to hematogenous seeding from recurrent diverticulitis that resolved after a 6-week course of intravenous antibiotics.

Clinically, the process to control her infection overshadowed her improvement from SI surgery.

Several years after her SI joint fusion, she was diagnosed with L3/4 adjacent segment disease and experienced partial pain relief after L3/4 laminectomy.

At the 5-year visit, there were no imaging findings to suggest implant failure as explanation for the subject's residual pain.

This subject reported symptoms in her contralateral SI joint and continuing symptoms from L3/4 that will likely require arthrodesis.

Therefore, the lumbar pain generators and symptoms from her contralateral SI joint have influenced the degree of her functional improvement after the index procedure.


All 7 patients with the SI joint as the sole PG experienced good to excellent outcomes.

In the 10 patients with multiple PGs, 7 had favorable outcomes while residual pain from secondary PGs eclipsed symptom relief in the remaining 3 patients.

There were no distinguishing characteristics on imaging between responders and non-responders.

Residual symptoms did not correlate with implant failure or lack of boney integration.

Accordingly, no correlation between clinical and radiographic outcomes can be made.


The 5-year results of patients treated for degenerative sacroiliitis and/or SI joint disruptions with MIS SI joint fusion using a series of triangular TPS coated implants presented herein demonstrate the long-term durability of positive outcomes regarding pain relief, return to function, and satisfaction with surgery.

Though pre-operative ODI scores were unavailable for the current case series, the published range for patients with SI joint disorders is 52.6- 61.8 [23, 24, 31].

Our mean 5-year postoperative ODI score (21.5) indicates minimal to moderate impact on functional capacity, and is commensurate with results from other published studies.

Long-term complications of MIS SI joint fusion were rare.

No subject underwent revision of SI joint arthrodesis.

Similar to other reports, a large portion (47%) of patients in the present cohort had a history of previous lumbar spinal fusion.

In contrast to a report describing the use of hollow modular anchorage screws, the degree of pain improvement for patients in the current study was not affected by a history of prior lumbar spinal fusion [19].

As with all studies, we observed variations in patient outcomes.

In the current cohort, the number of pain generators, either single or multiple, influenced patient perception of improvement in pain and function after surgery.

Amongst subjects who did not respond, multiple pain generators (PG) were apparent.

Determination of primary versus secondary pain generators is critical in patients that present with multiple PGs.


Imaging studies at 5 years postoperatively revealed no evidence of implant loosening, confirmed by a consistent observation of increased bone density immediately adjacent to all walls of all implants, suggestive of biological fixation in bone.

The cause of the sclerotic bony margin often observed on the upper wall of the most cranial implant is unknown, but may be the result of a) impaction from broaching step of the procedure, b) micromotion after initial implant placement, or c) as a result of Wolff's law in response to higher loading conditions.

Further investigation is needed to fully understand the mechanism.

After close evaluation of the appearance of the implants on plain film radiographs and CT imaging, we have come to appreciate the difference between lucency along an implant wall and actual loosening of the device.

An observation of apparent linear lucency along the wall, nose or shoulder of the implant on x- ray did not correlate with true lucency on CT in the present study, but rather with an artifact generated by the titanium implant.

In our experience, true loosening of the implant will result in the appearance of an enlarged gap between the implant and a sclerotic margin on both x-ray and CT (Fig. 7).

If implant loosening is suspected, it is vital to correlate clinical symptoms with 3 views on CT to differentiate artifact, lucency and loosening.


Multiple non-surgical and surgical treatments for SI joint disorders are available.

When non-surgical management fails to provide adequate relief of symptoms, surgical arthrodesis is an option.

Published case series of various arthrodesis techniques (both open and MIS) report variable degrees of improvement in pain and function, with more invasive approaches reporting moderately high complications and non-unions [22].

MIS techniques overall report significant improvements in pain and function, but results vary with surgical technique and patient selection.


Positive clinical outcomes are based on accurate diagnosis and assessment of all potential pain generators in the lumbar spine, SI joint and hip.

Correctly diagnosing SI joint disorders requires a rigorous approach to arrive at an accurate diagnosis.

A detailed history, comprehensive physical examination, and an index of suspicion are required to formulate a differential diagnosis.

The practitioner utilizes imaging and diagnostic testing for the process of inclusion/exclusion of the different diagnostic possibilities.


Several pathophysiologic conditions that affect the lumbar spine-SI joint-hip axis can present similarly and typically low back pain patients have multiple pain generators.

Biomechanical studies clearly show an interdependent kinematic relationship within the lumbopelvic hip complex, with changes in one structure affecting degree of motion and load within the entire complex [32].

Therefore, the SI joint should be evaluated as a potential pain generator in patients who fail to improve or experience late non-mechanical failures after lumbar arthrodesis.


Pain and degeneration in the SI joint after lumbar arthrodesis has been reported to range between 43 and 75% [6, 30, 33, 34].

The relatively low success rate of spinal fusion, combined with the high incidence of diagnosable SI joint disorders in patients presenting with low back pain strongly suggests that the SI joint is often overlooked as a PG in this population [3].


An accurate diagnosis requires not only a ruling out or downgrading of other conditions, but also a thorough evaluation of the lumbar spine and hip, as well as a physical exam that includes maneuvers that stress the SI joint and a series of image-guided intra-articular diagnostic injections.


For patients with multiple pain generators, the most bothersome should be treated first to assess the true impact of the secondary pain generator(s).

Surgical treatment of the primary PG alone may effectuate adequate pain control in certain patients, while for others sequential treatment of secondary PGs may be indicated to achieve a satisfactory 382 The Open Orthopaedics Journal, 2014, Volume 8 Rudolf and Capobianco final outcome.

Patients with multiple pain generators, regardless of treatment, may not experience a high degree of improvement as the cortical region of the sensory homunculus governing the low back and hip is relatively small, making it difficult for the brain to distinguish discrete pain generators in this area [35].

Functional improvement relies on the interdependent relationship of the lumbar spine, pelvis and hip axis.

Pain or loss of function in one component can overshadow improvement in another.

Identification and sequential treatment of secondary pain generators in this axis may be needed to achieve the best possible outcome.


Although the study sample size is relatively small and represents the experience of a single surgeon, this cohort represents the first patients to have received this implant.

ODI was available only at the 5-year time point; a comparison to baseline could not be performed.

It should be noted, however, that all pain and functional outcomes were self-reported by study subjects.

Larger cohort and multi- center long-term studies are needed to better understand how to formulate a surgical strategy and set realistic outcome expectations in the patient with multiple pain generators within the lumbar spine-SI joint-hip axis.


Long-term (5-year) clinical and radiographic outcomes after MIS SIJ fusion for degenerative sacroiliitis and/or SI joint disruptions are favorable.

Clinical improvements observed at 12 months postoperatively were maintained at 5years.

There was no evidence of long-term complications, implant migration or loosening.

Increased bone density was observed circumferentially in 100% of the implants.

Most (87%) scans showed intra-articular osseous bridging.

Patients who did not do well were affected by multiple severe degenerative conditions of the spine, pelvis, and/or hip.


LR is an SI-BONE, Inc. investor, consultant and clinical trial investigator.

RC is an SI-BONE, Inc. employee.


The sacroiliac joint (SIJ) may be a source of chronic low back pain in 15-22% of patients.


Over the past four years, minimally invasive surgery (MIS) has become an emerging standard of care for SI joint fusion.


The International Society for the Advancement of Spine Surgery (ISASS) and Society for Minimally Invasive Spine Surgery (SMISS) conducted a survey of their members to examine current preferences in surgeon practice of MIS SI fusion.


To qualify for survey participation, the surgeon had to perform at least one open or MIS SIJ fusion procedure between 2009 and 2012.


All surgeons were instructed to review their records.


This included the number of surgical procedures performed annually from 2009-2012, site of service where each procedure was commonly performed, and average length of stay for each approach.


Twenty-four percent (121/500) of the eligible members participated in this survey.


This survey revealed that the percentage of MIS procedures increased from 39% in 2009 to over 87% in 2012.


The survey showed a significant increase in the average number of MIS surgeries and a significant difference between open and MIS surgeries in 2012 (p<0.0001).


In addition, 80% of the survey respondents indicated a lack of preference toward the open approach if that was the only available option.


According to the performed survey, MIS SIJ fusion is preferred over the open technique.


Incorporation of the MIS technique into the spine surgeon's spectrum of skills would allow an increased number of surgical options as well as a possible increase in outcome quality.


Sacroiliac joint dysfunction, caused by degenerative sacroiliitis or sacroiliac disruption, has been recognized as a legitimate pain generator since the 1800s, but has remained under-appreciated and under-treated until the emergence of advanced diagnostic methods as well as the development of reasonable, effective, and less morbid interventional modalities.


Sacroiliac Joint (SI joint) pain is a significant cause of low back pain [1-3].


It has been reported as the pain generator in 15%-22% of patients with low back pain [1,4].


Non-operative management such as physical or manual therapy and fluoroscopic guided steroid injections are the first line treatment and in many cases the definitive treatment [4-6].


When non-operative management fails and SI joint symptoms persist, arthrodesis becomes a viable option.


A variety of surgical techniques have been developed to fuse the SI joint, including traditional open arthrodesis with plates and/or screws.


Emerging minimally invasive techniques have been developed because of potential advantages such as minimizing soft-tissue trauma, less operative blood loss, faster rehabilitation, and reduced length of hospital stay [7-9, 11, 13, 14].


Surgeons should choose the approach that will provide the best clinical outcome for the patient and treat their medical condition with the least risk of complications.


Since the development of instrumentation allowing SI joint fusions via a less invasive approach, the number of open procedures has significantly declined because the surgeon community appears to prefer the minimally invasive approach in the best interest of their patients [18].


Over the past four years, MIS is an emerging standard of care for SI joint fusion.


The International Society for the Advancement of Spine Surgery (ISASS) and Society for Minimally Invasive Spine Surgery (SMISS) conducted a survey of their members to examine current preferences in surgeon practice of MIS SI fusion.


Previous reports of minimally invasive (MIS) sacroiliac (SI) joint fusion for low back, SI joint, and buttock pain secondary to SI joint disorders have shown favorable short- and mid-term outcomes.

Herein we present 5-year clinical and radiographic outcomes after MIS SI joint fusion using a series of triangular porous titanium plasma spray (TPS) coated implants.

Consecutive patients treated with MIS SI joint fusion for degenerative sacroiliitis and/or sacroiliac joint disruptions between October 2007 and March 2009 were evaluated.

Pain on VAS, an SI joint specific survey and Oswestry Disability Index (ODI) were administered.

X-ray and CT scans were obtained to assess the implants.

Of 21 patients treated, 17 were available for the study.

Mean age was 58 years (range 36-85), 77% were female and 47% had prior lumbar spinal fusion.

Pain on VAS improved from 8.3 at baseline to 2.4 at 5 years; 88% of patients reached Substantial Clinical Benefit.

Mean ODI score at 5 years was 21.5 (SD 22.7).

Patient satisfaction achieved at 12 months was maintained for 5 years (82%).

A qualitative review of x-ray and CT imaging showed increased bone density immediately adjacent to all implants, intra-articular osseous bridging in 87% of patients and no evidence of implant loosening or migration.

Long-term clinical and radiographic outcomes after MIS SIJ fusion are favorable.

Clinical improvements observed at 12 months postoperatively were maintained at 5 years.

There was no evidence of long-term complications, implant loosening or migration.

Patients who did not achieve large improvements were affected by multiple severe concomitant degenerative conditions of the lumbar spine, pelvis, and/or hip.


Chronic lower back pain is well known as a public health epidemic.

In highly developed countries, it is one of the top 3 causes of degradation in quality adjusted life years, along with ischemic heart disease and chronic obstructive pulmonary disease [1].

While lumbar spine pathology is an important cause of chronic lower back pain, substantial evidence suggests that not all low back pain is due to lumbar spine pathology.

The SI joint is thought to be the source of pain in up to 30% of patients evaluated for chronic lower back pain [2-5].

Disorders of the SI joint may be the result of trauma, pregnancy, inflammatory arthritis, osteoarthritis or degeneration of the joint either de novo or after lumbar spinal fusion [6].

In the case of lumbar spinal arthrodesis, sacroiliac joint pathology may explain delayed postoperative pain or a failure for the patient to experience symptom improvement in the early postoperative period (failed back surgery syndrome) [7, 8].

Diagnosing the SI joint as the primary or sole pain generator (PG) can be complex as patients often present with a combination of low back, groin, gluteal, and/or leg pain and the symptom profile may mimic other disorders of the lumbar spine and hip [2, 9].

Additionally, some patients present with more than one pain generator within the lumbar spine-SI joint-hip axis, making the identification of the primary versus secondary pain generators more challenging [3].

Furthermore, SI joint imaging studies are typically neither sensitive nor specific to abnormalities in the absence of trauma, tumor, ankylosing spondylitis, or infection [10].

SI joint pain can be debilitating and treatment with non-operative care is often unsuccessful.

The impact of pain on persons living with the disease is similar to that associated with other prominent orthopedic conditions routinely treated surgically [11].

Furthermore, the economic burden of non-operative care is significant for Medicare as well as commercial payer entities with a 5-year estimated cost of $270 million for Medicare beneficiaries and a 3-year estimated cost of $1.6 billion per 100,000 commercial covered lives [12, 13].

Surgical treatment options for SI joint disorders have been unattractive until relatively recently.

Open arthrodesis, commonly performed throughout the 1900s, is now reserved primarily for traumatic pelvic ring fractures due to the invasiveness of the procedure, coupled with a high morbidity rate [14-16].

In recent years, several minimally invasive techniques for fusing the SI joint have been introduced into the surgical repertoire [17-21].

MIS SI joint fusion for certain SI joint disorders (degenerative sacroiliitis and SI joint disruptions), specifically using a series of triangular titanium implants, has been shown to result in lower morbidity, including shorter operating times and hospital stays, fewer complications, a lower reoperation rate, and higher gains in patient quality of life compared to the open surgical method, as evidenced by a recent comparative cohort study [22].

The current body of medical literature substantiates positive short to mid-term clinical outcomes [17, 23-25].

However, no long-term clinical or radiographic outcomes have been published to date.

Herein we report 5-year clinical effectiveness, safety and radiographic outcomes in patients treated with MIS SI joint fusion for degenerative sacroiliitis or sacroiliac joint disruptions using a series of triangular, porous titanium plasma spray (TPS) coated implants (iFuse Implant System®, SI-BONE, Inc., San Jose, CA) from a single center.


All consecutive patients who underwent MIS SI joint fusion between October 2007 and March 2009 at a single center were identified.

Prior to surgery, all patients were diagnosed with either degenerative sacroiliitis and/or SI joint disruptions using a detailed history, combination of physical provocative maneuvers specific to the SI joint, image-guided intra-articular SI joint injections and various imaging modalities [17].

MIS SI joint fusion was performed in all patients by placing a series of implants laterally across the SI joint, as previously described [17, 23].

Patients were contacted and asked to participate in a long-term evaluation, which included a clinical exam as well as an optional radiographic imaging component.

Patients signed a study-specific, IRB-approved consent form before beginning any study-related activity.

Patients were asked to reveal and discuss any further surgical treatment they received for SI joint, lumbar spine, pelvic or hip disorders.

A series of patient reported outcome instruments, described below, was also administered.

Participants who resided outside of a reasonable travel distance were given the opportunity to provide responses by phone or mail.

Patients who consented to the radiographic component of the study had both plain film radiographs (outlet and anteroposterior (AP) views) and computed tomography (CT) scans of the pelvis.

These imaging tests were used to assess implant position, evidence of lucency adjacent to the implant, qualitative increase in bone density adjacent to the implant, and presence of intra-articular osseous bridging.

The 5-year images were compared to those previously acquired closest to the one-year follow-up interval.

Data extracted from the medical charts included demographics, diagnosed pain generators in the lumbar spine-SI joint-hip axis, pain treatments received, perioperative measures, adverse events, one-year imaging studies, and previously administered patient reported outcomes at 12- and 24-months postoperatively, described below.


Pain and functional outcomes were assessed in a prospective manner pre-operatively and at 12-, 24- and 60-months postoperatively.

Level of pain was assessed using a 0-10 visual analog scale (VAS).

Prior to the initial experience with the surgical procedure, a 9-question SI joint-related health outcomes survey was created with response domains taken from both the SF-36 and Oswestry Disability Index (ODI) (Fig. 1): pain level, the ability to perform light, moderate and vigorous activities, quality of sleep, lifting ability, happiness, social activities, and the effect of pain on social life [17].

A numerical rating scale of 0-10 with 0 representing no pain or difficulty and 10 representing the worst pain imaginable or severe difficulty was used for all domains.

Satisfaction with surgery was assessed in a binary fashion (yes or no) by asking if the patient would have the same surgery again for the same result.

The SI joint-related health outcomes survey and VAS were administered preoperatively and at 12- and 60-months postoperatively.

At 24 months, patients were contacted to assess SI joint pain on VAS.

The ODI was administered at the 60-month visit only.

Satisfaction and safety events were collected at all postoperative time points.

Demographic variables were tabulated and expressed as frequency and means with standard deviation, where appropriate.

A repeated measures analysis of variance (ANOVA) was used to compare VAS pain scores from baseline to all postoperative time points.

A paired t-test was used to assess improvement from baseline to the 60-month time point on the SI joint survey.

An unpaired t-test was performed to assess the effect of sex and history of prior lumbar spinal fusion on outcomes.

Statistical analyses were performed using R software [26].

Clinical improvement was defined using previously validated minimum clinically important difference (MCID) and substantial clinical benefit (SCB) values for back pain on VAS.

MCID is defined as a change of >2.0 points and SCB is defined as a 2.5-point decrease or a raw score of < 3.5 [27, 28].

Institutional Review Board approval was obtained before beginning this study.


Of 21 consecutive patients who underwent MIS SI joint fusion, 17 were available for follow-up and form the analysis cohort.

Of those not available, 2 had died unrelated to spine conditions, one was lost to follow-up and one suffered a severe neck trauma rendering the patient quadriplegic and unable to provide relevant data.

All available patients participated in the clinical portion of the study and 15 of 17 (88%) agreed to participate in the radiographic component.

Mean subject age was 58 (±14) years (range 36-85), 77% were female and 47% had undergone lumbar spinal fusion prior to SI joint fusion (Table 1).

Slightly more subjects had the right SI joint treated (53%) compared to the left (41%), and one patient underwent bilateral treatment.

Mean operating time was 65 (±18) minutes, range (43-110).

There were no intraoperative complications.

Postoperative events, which primarily included hematoma (1), cellulitis (2), and deep infection secondary to diverticulitis (1), were previously reported in detail [17].

Improvement in pain was clinically and statistically significant at all follow-up intervals compared to baseline (all p<0.001) (Table 2).

All subjects who reached MCID also reached SCB.

The percentage of patients who achieved both MCID and SCB remained high at each time point (77%, 82%, and 88% at 12-, 24- and 60-month visits, respectively).

No statistical effect was found for sex, or history of lumbar fusion on pain improvement at any time point.

At 60-months, statistically significant improvement was seen in 6 of 8 domains of the SI joint survey instrument (Table 3): the ability to perform light, moderate and vigorous activities, sleep disturbance caused by pain, overall happiness, and the effect of pain on social life.

The ability to perform light, moderate and vigorous activities showed continual improvement from 12 months to the 5-year time interval.

Patient satisfaction scores obtained at the 12-month interval were unchanged at 2- and 5-years postoperatively; 82% (14/17) would have the same surgery again for the same result at all time points.

ODI scores were obtained at the 5-year follow-up only (Table 4).

Mean (SD) ODI score was 21.5 (22.7).

Fairbank categorized scores in terms of degree of disability, with 0-20 representing minimal disability and 21-40 representing moderate disability requiring conservative care only [29].

Results show the majority (71%) of subjects are living with minimal or moderate disability.


Pelvic AP and outlet view plain films radiographs and a pelvic computed tomography (CT) scan were performed on 15 subjects; 45 implants were assessed.

Imaging studies obtained at 5 years were compared to available studies acquired as close as possible to the one-year postoperative time point.

A qualitative comparison of 1- and 5-year pelvic plain film radiographs, including AP and outlet views, revealed no change in implant position (Fig. 2).

CT scans of the pelvis with axial, sagittal, and coronal reconstructions documented increased bone density circumferentially along three implant walls for all implants on both the iliac and sacral segments.

Evidence of osseous bridging across the SI joint was clearly seen on 13 of 15 (87%) of patients (Fig. 3).

On x-ray, what appeared to be full-length lucency (absence of bone adjacent to an implant) along the wall of the implant was consistently observed on at least one implant in all patients on AP view.

However, this observation was not evident on the outlet view.

Upon review of CT imaging, this apparent lucency was confirmed to be an artifact (Fig. 4).

Assessment and comparison of CT scans at 1- and 5-years revealed a consistent pattern of artifacts at the corners and periodically along the wall of an implant, which were non-progressive and unchanged in equivalent projections on the axial, sagittal and coronal sections.

A small area of true focal lucency was observed on CT scans in 4 patients; along the superior edge of the most cranial implant on the iliac side in 3 patients, and on the superior edge of the most caudal implant on the iliac side in one patient (Fig. 5).

Other findings included a regular pattern of sclerotic bone response at the implant entry point in the ilium, on primarily the superior implant (Fig. 6).

A detailed explanation of the physics of CT imaging of triangular titanium implants is outside the scope of this manuscript and will be reported separately.


Three subjects in the current cohort did not improve satisfactorily.

To understand why these patients failed to improve and to refine patient selection criteria for MIS SI joint fusion, an in-depth interview was performed for each patient.

Patient vignettes are described below.

Subject 1012 is a 72-year old woman who presented to the clinic complaining of low back and pelvic pain.

The subject’s history included a successful total knee replacement as well as L3-L5 arthrodesis for degenerative thoracolumbar scoliosis, symptomatic spondylosis and spondylolisthesis.

At baseline, the lumbar spine and SI joint were confirmed as pain generators using physical and clinical exam, imaging studies, and injections as appropriate.

Non-operative management was employed for lumbar spinal pain.

Based on the pain improvement associated with image-guided intra-articular SI joint injection, MIS SI joint fusion was performed without postoperative complications.

After surgery, she continued to have persistent back pain and buttock pain with walking.

Subsequent imaging studies revealed a progression of her scoliotic curve above L3 with pelvic obliquity and clinical exam suggested multiple pain generators including thoracolumbar spine and degenerative joint disease of the hip.

Pelvic and spinal radiographs at the 5-year visit, and comparison to imaging at 1-year, revealed her SI implants to be intact with no signs of loosening, and a progression of spondylosis at levels above L3.

The 5-year pelvic CT scan showed increased bone density along the walls of the implants, suggestive of biological fixation of the implants in bone.

There were no imaging findings to suggest implant failure as explanation for the subject’s residual pain.

In addition to her SI joint problems, this patient suffers from multiple pain generators including hip dysfunction secondary to pelvic obliquity and spondylosis associated with degenerative scoliosis.

A review of this case provokes concern that the symptomatology of other pain generators may have overshadowed any potential improvement after SI joint treatment.

Results from a single image guided intra-articular SI joint injection may be vulnerable to misinterpretation in the context of multiple pain generators.

Some patients may benefit from a second injection.

Positive results on the second injection will confirm the SI joint as the primary PG.

However, an equivocal response of less than 75% pain reduction would suggest the SI joint as a secondary PG [30].

No pain improvement rules out the SI and indicates that other PGs in the lumbar spine-SI joint-hip axis need further investigation.


Subject 1013 is a 50-year old female who presented to the clinic post L4-S1 arthrodesis with complex pain syndrome and concomitant chronic conditions requiring multiple medications to manage her pain.

Furthermore, due to her diminished ambulatory capability, she required assistance in performing activities of daily living.

Subject symptoms and findings on physical exam suggested degenerative sacroiliitis.

The SI joint as a pain generator was confirmed by intra-articular SI joint injection.

The subject underwent a single-side SI joint fusion.

She experienced good pain improvement on the operative side, prompting her to undergo diagnostic testing on the contralateral side followed by SI joint fusion.

Postoperatively, she experienced significant improvement in ambulation and capacity for activities of daily living and near complete resolution of her bilateral SI joint pain.

One year later, her degenerative hip joint disease had progressed, resulting in a left-sided total hip replacement.

This subject declined to participate in the imaging component of the study.

The degradation of function and high ODI score at the 5-year assessment seems associated with recurrent spine-related low back pain.


Subject 1002 is a 50-year old female who underwent left SI joint fusion for degenerative sacroiliitis after previous L4-S1 instrumented arthrodesis for degenerative spondylosis and spondylolisthesis.

Postoperatively, she suffered from an infected hematoma secondary to hematogenous seeding from recurrent diverticulitis that resolved after a 6-week course of intravenous antibiotics.

Clinically, the process to control her infection overshadowed her improvement from SI surgery.

Several years after her SI joint fusion, she was diagnosed with L3/4 adjacent segment disease and experienced partial pain relief after L3/4 laminectomy.

At the 5-year visit, there were no imaging findings to suggest implant failure as explanation for the subject’s residual pain.

This subject reported symptoms in her contralateral SI joint and continuing symptoms from L3/4 that will likely require arthrodesis.

Therefore, the lumbar pain generators and symptoms from her contralateral SI joint have influenced the degree of her functional improvement after the index procedure.


All 7 patients with the SI joint as the sole PG experienced good to excellent outcomes.

In the 10 patients with multiple PGs, 7 had favorable outcomes while residual pain from secondary PGs eclipsed symptom relief in the remaining 3 patients.

There were no distinguishing characteristics on imaging between responders and non-responders.

Residual symptoms did not correlate with implant failure or lack of boney integration.

Accordingly, no correlation between clinical and radiographic outcomes can be made.


The 5-year results of patients treated for degenerative sacroiliitis and/or SI joint disruptions with MIS SI joint fusion using a series of triangular TPS coated implants presented herein demonstrate the long-term durability of positive outcomes regarding pain relief, return to function, and satisfaction with surgery.

Though pre-operative ODI scores were unavailable for the current case series, the published range for patients with SI joint disorders is 52.6-61.8 [23, 24, 31].

Our mean 5-year postoperative ODI score (21.5) indicates minimal to moderate impact on functional capacity, and is commensurate with results from other published studies.

Long-term complications of MIS SI joint fusion were rare.

No subject underwent revision of SI joint arthrodesis.

Similar to other reports, a large portion (47%) of patients in the present cohort had a history of previous lumbar spinal fusion.

In contrast to a report describing the use of hollow modular anchorage screws, the degree of pain improvement for patients in the current study was not affected by a history of prior lumbar spinal fusion [19].

As with all studies, we observed variations in patient outcomes.

In the current cohort, the number of pain generators, either single or multiple, influenced patient perception of improvement in pain and function after surgery.

Amongst subjects who did not respond, multiple pain generators (PG) were apparent.

Determination of primary versus secondary pain generators is critical in patients that present with multiple PGs.

Imaging studies at 5 years postoperatively revealed no evidence of implant loosening, confirmed by a consistent observation of increased bone density immediately adjacent to all walls of all implants, suggestive of biological fixation in bone.

The cause of the sclerotic bony margin often observed on the upper wall of the most cranial implant is unknown, but may be the result of a) impaction from broaching step of the procedure, b) micromotion after initial implant placement, or c) as a result of Wolff’s law in response to higher loading conditions.

Further investigation is needed to fully understand the mechanism.

After close evaluation of the appearance of the implants on plain film radiographs and CT imaging, we have come to appreciate the difference between lucency along an implant wall and actual loosening of the device.

An observation of apparent linear lucency along the wall, nose or shoulder of the implant on x-ray did not correlate with true lucency on CT in the present study, but rather with an artifact generated by the titanium implant.

In our experience, true loosening of the implant will result in the appearance of an enlarged gap between the implant and a sclerotic margin on both x-ray and CT (Fig. 7).

If implant loosening is suspected, it is vital to correlate clinical symptoms with 3 views on CT to differentiate artifact, lucency and loosening.


Multiple non-surgical and surgical treatments for SI joint disorders are available.

When non-surgical management fails to provide adequate relief of symptoms, surgical arthrodesis is an option.

Published case series of various arthrodesis techniques (both open and MIS) report variable degrees of improvement in pain and function, with more invasive approaches reporting moderately high complications and non-unions [22].

MIS techniques overall report significant improvements in pain and function, but results vary with surgical technique and patient selection.

Positive clinical outcomes are based on accurate diagnosis and assessment of all potential pain generators in the lumbar spine, SI joint and hip.

Correctly diagnosing SI joint disorders requires a rigorous approach to arrive at an accurate diagnosis.

A detailed history, comprehensive physical examination, and an index of suspicion are required to formulate a differential diagnosis.

The practitioner utilizes imaging and diagnostic testing for the process of inclusion/exclusion of the different diagnostic possibilities.

Several pathophysiologic conditions that affect the lumbar spine-SI joint-hip axis can present similarly and typically low back pain patients have multiple pain generators.

Biomechanical studies clearly show an interdependent kinematic relationship within the lumbopelvic hip complex, with changes in one structure affecting degree of motion and load within the entire complex [32].

Therefore, the SI joint should be evaluated as a potential pain generator in patients who fail to improve or experience late non-mechanical failures after lumbar arthrodesis.

Pain and degeneration in the SI joint after lumbar arthrodesis has been reported to range between 43 and 75% [6, 30, 33, 34].

The relatively low success rate of spinal fusion, combined with the high incidence of diagnosable SI joint disorders in patients presenting with low back pain strongly suggests that the SI joint is often overlooked as a PG in this population [3].

An accurate diagnosis requires not only a ruling out or downgrading of other conditions, but also a thorough evaluation of the lumbar spine and hip, as well as a physical exam that includes maneuvers that stress the SI joint and a series of image-guided intra-articular diagnostic injections.

For patients with multiple pain generators, the most bothersome should be treated first to assess the true impact of the secondary pain generator(s).

Surgical treatment of the primary PG alone may effectuate adequate pain control in certain patients, while for others sequential treatment of secondary PGs may be indicated to achieve a satisfactory final outcome.

Patients with multiple pain generators, regardless of treatment, may not experience a high degree of improvement as the sensory region of the cortical homunculus governing the low back and hip is relatively small, making it difficult for the brain to distinguish discrete pain generators in this area [35].

Functional improvement relies on the interdependent relationship of the lumbar spine, pelvis and hip axis.

Pain or loss of function in one component can overshadow improvement in another.

Identification and sequential treatment of secondary pain generators in this axis may be needed to achieve the best possible outcome.

Although the study sample size is relatively small and represents the experience of a single surgeon, this cohort represents the first patients to have received this implant.

ODI was available only at the 5-year time point; a comparison to baseline could not be performed.

It should be noted, however, that all pain and functional outcomes were self-reported by study subjects.

Larger cohort and multi-center long-term studies are needed to better understand how to formulate a surgical strategy and set realistic outcome expectations in the patient with multiple pain generators within the lumbar spine-SI joint-hip axis.


Long-term (5-year) clinical and radiographic outcomes after MIS SIJ fusion for degenerative sacroiliitis and/or SI joint disruptions are favorable.

Clinical improvements observed at 12 months postoperatively were maintained at 5years.

There was no evidence of long-term complications, implant migration or loosening.

Increased bone density was observed circumferentially in 100% of the implants.

Most (87%) scans showed intra-articular osseous bridging.

Patients who did not do well were affected by multiple severe degenerative conditions of the spine, pelvis, and/or hip.


GMAA appears of some benefit in UC.

High-quality RCTs comparing GMAA with conventional medical therapy or sham procedure in Western populations, with disease activity confirmed endoscopically, are required.


Rationale 3 Describe the rationale for the review in the context of what is already known.


A search of the medical literature was conducted using MEDLINE (1950 to August 2010), EMBASE (1946 to August 2010), and the Cochrane central register of controlled trials.

Randomised controlled trials examining the efficacy of GMAA in adult patients (> 90% over 16 years of age) with active or corticosteroid-dependent UC were eligible for inclusion.

The control arms of these trials were required to receive any of conventional medical therapy, sham apheresis procedure, or an alternative regimen using an active GMAA column.

Trials that permitted other concomitant therapies were eligible, as long as these were administered to both the intervention and control arms.

The primary outcome studied was remission of disease activity.

Secondary outcomes, where reported, included response to therapy, if remission rates were not described, effect of GMAA on endoscopic healing and quality of life, evidence of any corticosteroid-sparing effects, and adverse events arising as a result of GMAA.


Studies of GMAA in UC were identified with the terms ulcerative colitis, inflammatory bowel disease, proctitis, or colitis (both as medical subject headings (MeSH) and free text terms).

These were combined using the set operator AND with studies identified with the terms: blood component removal, leukapheresis, monocytes, or granulocytes (both as MeSH and free text terms), or granulocyte apheresis, monocyte apheresis, or adacolumn (as free text terms).


Abstracts of the papers identified by the initial search were evaluated by the lead investigator for appropriateness to the study question.

All potentially relevant papers were obtained and evaluated in detail.

The bibliographies of all identified Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w relevant studies were used to perform a recursive search of the literature.

Articles were assessed independently by two investigators using pre-designed eligibility forms, according to the eligibility criteria stated previously.

Any disagreement between investigators was resolved by discussion with a third investigator.


All data were extracted independently by two investigators on to a Microsoft Excel spreadsheet (XP professional edition; Microsoft Corp, Redmond, WA, USA) as dichotomous outcomes (i.e. remission / response or failure of remission / response).

In addition, the following clinical data were extracted for each trial, where available: number of centres, country of origin, geographical region, UC characteristics (severity of UC activity, presence of corticosteroid-dependence or resistance), schedule of GMAA used, duration of therapy, primary outcome measure used to define remission or response following therapy, and duration of follow-up.


This was performed independently by two investigators, with disagreements resolved by discussion with a third investigator.

Risk of bias was assessed as described in the Cochrane handbook, 23 by recording the method used to generate the randomization schedule, the method used to conceal allocation, whether blinding was implemented, what proportion of patients completed follow-up, whether an intention- to-treat analysis was extractable, and whether there was evidence of selective reporting of outcomes.


The search strategy identified a total of 1729 citations, 16 of which appeared to be relevant to the study question, and were therefore retrieved and evaluated in more detail (Figure 1).

Nine articles, 24-32 reporting the results of ten separate RCTs, were eligible for inclusion in the systematic review.

We did not perform a formal meta- analysis due to concerns about the high risk of bias among the RCTs we identified.


Individual trial characteristics are provided in Table 1.

Four trials compared GMAA with conventional medical therapy, 24, 25, 31, 32 two separate trials (reported in a single article) compared GMAA with sham apheresis, 26 and four trials compared "intensive" versus "conventional" GMAA regimens.

27-30 Only two trials were at low- risk of bias according to our assessment.

26 Six studies were conducted entirely in Japan, 24, 25, 27, 28, 31, 32 two in Europe, 29, 30 one in the USA and Canada, 26 and one in both Europe and Japan.

26 Eight of the trials reported remission rates, 24-30 while the remaining two reported response rates to therapy.

31, 32 Six RCTs performed a true intention-to-treat analysis, with dropouts assumed to be treatment failures.

24-26, 28, 31


We identified four trials making this comparison, all of which were conducted in Japanese centres.

24, 25, 31, 32 The first, 32 published in 1999, randomised 120 patients with UC in equal numbers to receive either five GMAA sessions over 5 weeks or standard medical therapy with corticosteroids.

Follow-up was for 7 weeks and 105 patients completed the trial.

The authors reported that 31 (58.5%) of 53 patients assigned to GMAA column responded, compared with 23 (44.2%) of 52 allocated to Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w standard medical therapy (P = 0.045).

Corticosteroid-sparing effects and adverse events data were not reported.


In a smaller study, Hanai and colleagues recruited 69 patients with corticosteroid-dependent UC.

24 The active intervention was 11 sessions of GMAA given over 10 weeks, while the control arm received a mean dose of 30mg/day of oral prednisolone.

The primary outcome reported by the authors was clinical remission, defined using a clinical activity index of ≤ 4 and a visible mucosal vascular pattern at endoscopy.

Data were also collected concerning any corticosteroid-sparing effects of GMAA therapy, cumulative corticosteroid doses, and mean corticosteroid dose at last point of follow-up of the trial, which was 24 weeks.

Remission occurred in 39 (84.8%) of 46 allocated to GMAA, compared with 16 (69.6%) of 23 randomised to corticosteroids (P = not significant).


Overall, 10 (21.7%) of the apheresis patients were corticosteroid-free at 24 weeks, compared with 3 (13.0%) of those receiving prednisolone (P = not significant).

Cumulative corticosteroid doses were significantly lower at the end of treatment in the GMAA patients (P = 0.001), and mean corticosteroid dose was also significantly lower (P = 0.003).

Adverse events were reported by 10 patients receiving GMAA, with flushing in six patients.

Adverse events among those assigned to corticosteroids were not reported.


Nakamura and colleagues recruited 20 patients with active UC, 31 all of whom were receiving corticosteroids at study commencement, and randomised them in equal numbers to either GMAA or conventional medical therapy with corticosteroids.

They used a combination of clinical symptoms, endoscopic appearance, and inflammatory markers to define response to therapy.

There was a response rate of 80.0% in the GMAA arm of the trial, compared with 20.0% in the conventional treatment patients (P < 0.05), and the proportion of patients reporting blood in the stools after Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w completion of therapy was significantly lower in those receiving GMAA (10.0% versus 70.0%, P < 0.01).

Corticosteroid-sparing effects and adverse event rates were not reported by the authors.


The most recent RCT making this comparison was conducted at 5 centres in Japan.

25 The investigators randomised 70 patients with severely active UC, most of whom were receiving 5-ASAs in combination with low-dose prednisolone, to receive either twice-weekly GMAA for weeks followed by weekly GMAA, up to a maximum of 11 sessions in total, or intravenous prednisolone at a dose of 40 to 60mg/day for 5 to 10 days, followed by tapered oral prednisolone.

Corticosteroid- dependent patients in both treatment arms also received mercaptopurine.

Follow-up was at 12 weeks, and the primary outcome measure was clinical remission, defined using a clinical activity index of ≤ 4.

The authors also reported the numbers of patients achieving a corticosteroid-free remission, and adverse events rates.

Overall, 26 (74.3%) of 35 in the GMAA arm achieved remission, compared with 16 (48.6%) of 35 receiving prednisolone (P = 0.02).

In addition, 27 (77.1%) of the GMAA patients were corticosteroid-free at 12 weeks, compared with 5 (14.3%) of the patients receiving prednisolone (P = 0.008).

Finally, only 5 (14.3%) GMAA patients reported adverse events, compared with 29 (64.4%) of those receiving corticosteroids.


There were two RCTs comparing GMAA with a sham apheresis procedure, reported in a single article.


The larger of these two trials was conducted in the USA and Canada, and recruited 168 patients with moderate to severely active UC who were already receiving treatment with at least one of 5-ASA, corticosteroids, azathioprine, or mercaptopurine.

Participants were treated for 9 weeks, and the primary outcome of Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w interest was the number of individuals achieving clinical remission, defined using a Mayo score of or less, at weeks post-randomisation.

Secondary outcome measures included endoscopic remission, and change in quality of life from baseline.

Overall, 19 (17.0%) of 112 patients were in clinical remission at 12 weeks with GMAA compared with 6 (10.7%) of 56 receiving the sham apheresis procedure (P = 0.36).

The proportion of patients achieving endoscopic remission was very similar in both treatment arms (12% versus 11%, P = 1.0).


The smaller trial was of identical design, and recruited 47 UC patients from 11 European and 1 Japanese centre.

Clinical remission occurred in 5 (16.1%) of 31 and 3 (18.8%) of 16 in the GMAA and sham apheresis arms respectively.

Changes in quality of life scores from baseline were not reported in detail, but were said to be comparable between active intervention and control patients in both trials.

Serious adverse events were reported in 14% of all GMAA and 11% of all sham apheresis patients.


Given the perhaps unexpected finding that GMAA was not significantly superior to sham apheresis in achieving clinical remission in active UC, the authors conducted a subgroup analysis, which included only the 63 patients with histological evidence of mucosal erosions or ulceration at baseline.

Clinical remission was achieved in 11 (24%) of the 46 of these individuals who received GMAA versus 0 (0%) of the 17 randomised to sham apheresis (P = 0.03).

These data suggest that GMAA is of benefit in patients with confirmed endoscopically active disease, and that the treatment effect may have been diluted by the inclusion of patients with much milder disease, or perhaps even functional symptoms.


There were four RCTs that compared "intensive" GMAA regimens with "conventional" regimens.

27-30 Ricart et al. randomised 20 UC patients with moderately active disease, all of whom were corticosteroid-dependent, to either 10 apheresis sessions over 10 weeks, or five sessions over 5 weeks.

29 The primary outcome was clinical remission, according to a clinical activity index of ≤ 4, at week 17.

Corticosteroid requirements and quality of life were also recorded.


In total, 19 patients completed the study.

In the "intensive" arm, 5 (45.5%) of 11 were in remission, compared with 3 (37.5%) of 8 in the "conventional" arm.

All those who achieved clinical remission were also in endoscopic remission, and all but one of these patients were corticosteroid-free at week 17.

Quality of life scores improved from baseline in both groups, but these differences were not statistically significant.

There were no serious adverse events observed in either arm of the trial.


In a small Japanese RCT conducted at a single centre, 28 30 patients with moderately active UC, 50% of whom were corticosteroid-dependent, were randomised to "intensive" GMAA, consisting of three sessions per week for 2 weeks followed by one session for 4 weeks, or "conventional" GMAA with 10 weekly sessions.

The primary endpoint was remission 1 week after the end of therapy (7 weeks follow-up for the "intensive" arm, versus 11 weeks for the "conventional"), defined using a clinical activity index of ≤ 4, as well as time (in days) to remission.

Changes in quality of life, corticosteroid dose, and endoscopic scores were also reported.

Overall, 12 (80.0%) of 15 in the "intensive" GMAA arm were in remission, compared with 10 (66.7%) of 15 in the "conventional" GMAA arm, but this difference was not statistically significant (P = 0.25).

However, time to remission was Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w significantly lower in those in the "intensive arm" (10.7 days versus 27.2 days, P = 0.04).

Again, there was no significant difference observed in quality of life scores, and there were no significant differences in endoscopic scores between the two arms.

Corticosteroid doses were significantly lower at the end of treatment, compared with baseline, in both arms (P = 0.03 for both).

There were four adverse events observed, two in each group.


A multi-centre Japanese RCT compared twice-weekly with weekly GMAA, up to a maximum of 10 sessions, in 163 UC patients with mildly to moderately active disease.

27 The primary outcome measure was clinical remission, again defined using a clinical activity index of ≤ 4, at 5 weeks in the "intensive" arm and 10 weeks in the "conventional" arm.

Time to remission was also compared between the two treatment regimens.

In total, 149 patients provided analysable data at study end.

The remission rate was higher in the "intensive" therapy arm of the trial, 71.2% (52 of 73) versus 54.0% (41 of 76) in the "conventional" arm (P = 0.03), and time to remission was significantly lower in the "intensive" therapy arm (14.9 days versus 28.1 days, P < 0.001).

Adverse events occurred in similar numbers of patients in each arm of the trial (17 in "intensive" versus 14 in "conventional"), but none were serious.


The largest RCT, to date, to compare "intensive" with "conventional" GMAA was conducted in 42 centres in Europe and recruited 186 patients with moderately to severely active corticosteroid-dependent or resistant UC.

30 The "intensive" arm received twice-weekly apheresis for 2 weeks followed by a further six sessions over 6 weeks.

In the "conventional" arm GMAA was administered weekly for 5 weeks.

All patients were already receiving treatment with one or more of 5-ASA, corticosteroids, azathioprine, or mercaptopurine, unless previous intolerance or non-response to these drugs had been demonstrated.

The primary outcome of interest was clinical remission Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w at 12 weeks, according to a clinical activity index ≤ 4, with 162 patients providing data for this analysis.

Time to remission and endoscopic activity were also reported.

Remission rates in the two arms were almost identical (43.9% (36 of 82 patients) with "intensive" versus 40.0% (32 of 80 patients) with "conventional"), and there was no statistically significant difference observed in terms of time to remission (39.9 days versus 46.8 days) or in endoscopic activity.

Overall, 6% of the "intensive" therapy arm and 9% of the "conventional" arm experienced a serious adverse event.


This systematic review has collected all available published RCT evidence examining the effects of GMAA in both active and corticosteroid-dependent or resistant UC.

Compared with conventional medical therapy, in the form of corticosteroids, GMAA appeared superior in several respects.

Remission rates in excess of 70% were achieved with GMAA in patients with severely active UC, 25 which were significantly higher than those achieved with conventional medical therapy.


In corticosteroid-dependent UC, rates of remission with GMAA were as high as 85%.

24 There was also evidence for corticosteroid-sparing effects with GMAA, with significantly lower cumulative doses of corticosteroid, 24 and significantly higher rates of corticosteroid-free remission in patients allocated to GMAA.

25 In addition, adverse event rates were significantly higher in patients assigned to conventional medical therapy.


Compared with a sham apheresis procedure in patients with moderately to severely active UC, 26 GMAA did not achieve significantly higher rates of clinical or endoscopic remission, and adverse events rates were comparable.

However, when only individuals with evidence of mucosal erosions or ulceration at baseline histological examination were considered in the analysis, significantly higher remission rates were observed with GMAA.


In terms of "intensive" GMAA regimens versus "conventional" regimens, available data were conflicting.

Three trials suggested that "intensive" regimens were associated with generally higher rates of remission, 27-29 and time to achievement of remission was significantly shorter in two RCTs recruiting patients with mildly to moderately active UC.

27, 28 However, the largest RCT to date demonstrated almost identical remission rates with "intensive" and "conventional" regimens in corticosteroid-dependent patients with moderately to Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w severely active disease, and no statistically significant difference in the time to remission.


The effect of GMAA on quality of life was not studied in many of the eligible RCTs but, where reported, there appeared to be no significant benefit of GMAA over conventional medical therapy, sham apheresis procedure, or between the various "intensive" and "conventional" regimens.


Strengths of our study include our rigorous methodology.

We described our search strategy, eligibility criteria, and data extraction processes in detail.

In addition, independent data extraction was undertaken by two reviewers, and discrepancies were checked and resolved.

Finally, the majority of the trials we identified used a validated definition of remission as a clinical endpoint, rather than response to therapy, which we believe is a more clinically useful outcome to the physician who is considering GMAA as a treatment option in a patient with chronic active or corticosteroid- dependent UC who is unsuitable for, or refuses, surgery.


Limitations of the present study, as with any systematic review and meta- analysis, arise from the quality of the trials included.

Only two of the ten eligible and included RCTs were at low risk of bias, 26 and most trials did not report either the method used to generate the randomisation list, or whether allocation to treatment was concealed.

In addition, only three trials reported that investigators were blinded to the assigned therapy.

25, 26 It has been well-described in the systematic review literature that RCTs that do not adhere to such reporting of their methodology, and trials that are not blinded, tend to overestimate the treatment effect associated with the active intervention.

33 Only six trials reported data using a true intention-to-treat analysis.

24- 26, 28, 31 Again, this may have led to an overestimation of the success rates with active therapy.

A final limitation is the fact that six of the ten RCTs were conducted in Japan, meaning that their results may not be generalisable to a Western population, Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w due to potential underlying differences in patient characteristics, genetics, or environment.


There has been one previous systematic review to our knowledge, to date, that has examined the efficacy of GMAA in UC.

34 In contrast to the current study, the authors felt it appropriate to perform a meta-analysis.

They reported a statistically significant benefit of GMAA over control therapy, defined using either response to therapy or clinical remission, with a number needed to treat of 5, and concluded that homogeneous evidence from seven RCTs uniformly indicated that GMAA was more successful than drug therapy in achieving response and remission.

There are some limitations of this meta-analysis that we have discussed elsewhere, 35 including pooling of data from RCTs regardless of the control intervention, and the inclusion of a pseudo-randomised study in the analysis, 37 a type of study design that is liable to selection bias.

In addition, the largest RCT that they identified showed no significant effect of GMAA on remission or response.

26 There was also statistically significant heterogeneity between studies, 36 perhaps due to underlying differences in the GMAA regimens used in the various trials.


Data from the current study demonstrate some evidence for a benefit of GMAA over conventional medical therapy, in patients with either active or corticosteroid-dependent UC, in terms of clinical remission, corticosteroid-sparing effects, and reduced adverse events rates, but no trial to date making this comparison has been conducted in a Western population.

The only study to compare GMAA with a sham apheresis procedure, conducted in both Western and Japanese patients, failed to demonstrate any significant increase in remission rates with GMAA.

The authors speculated that their patient population may have differed from those in previous trials in terms of disease activity, and that GMAA may only be effective in patients with Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w severe histological activity, an assertion supported by their post hoc analysis discussed in detail earlier.

There seems to be little to choose between various GMAA regimens in terms of clinical remission rates, though time to remission may be shorter with a more "intensive" regimen.

Adverse events were no higher with GMAA in most studies, and serious adverse events were rare, suggesting it is a safe treatment option.

Finally, data to support any beneficial effect of GMAA on quality of life are sparse.


Taken together these data tell us that, rather than designing future RCTs to examine the potential benefit of one GMAA regimen over another, what is actually required are convincing high-quality data that GMAA is effective in Western patients with UC.

Trials comparing GMAA with conventional medical therapy in corticosteroid-dependent patients are needed to demonstrate that the results from Japanese trials are reproducible.

In addition, further rigorous RCTs, of similar design to that of Sands et al., 26 should compare GMAA with sham apheresis in patients with histological evidence of active disease.

One potential niche for GMAA is in patients with chronic subacute UC refractory to, or intolerant of, 5-ASAs or immunomodulators, who are corticosteroid-dependent, but who do not have acute severe disease, and who are therefore unsuitable for either infliximab or ciclosporin.


The only other treatment option at present for this type of patient is surgery, which may not be suitable, or desirable, for all individuals.

Therefore studies that compare quality of life in patients in this situation who receive GMAA or panproctocolectomy, followed by either end ileostomy or IPAA, would also be of great interest to both patients and physicians.


In summary, this systematic review has demonstrated some evidence for a beneficial effect of GMAA in active or corticosteroid-dependent UC, in terms of both clinical remission rates and corticosteroid-sparing effects, but more data from trials Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w conducted in Western patients with endoscopic evidence of active disease are required before its true place in the management of UC is known.


Sangeetha Thanaraj: none declared.

P. John Hamlin: has participated in an advisory board for Otsuka Pharmaceuticals.

Alexander C. Ford: none declared.


10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.


17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.