The Longitudinal Outcome of Fibromyalgia: A Study of 1555 Patients

Journal of Rheumatology, Jul 15, 2011;38(7).

The Longitudinal Outcome of Fibromyalgia: A Study of 1555 Patients.

Brian Walitt, Mary-Ann Fitzcharles, Afton L. Hassett, Robert S. Katz, Winfried Häuser
and Frederick Wolfe

Author Affiliations:

From Georgetown University, Washington Hospital Center, Washington, DC; Montreal General Hospital, Division of Rheumatology, McGill University, Montreal, Quebec, Canada; Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan; Rush University Medical Center, Chicago, Illinois; Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München, Munich, Germany; and the National Data Bank for Rheumatic Diseases and University of Kansas School of Medicine, Wichita, Kansas, USA.

ABSTRACT

OBJECTIVE:
To describe the diagnosis status and outcome of patients diagnosed with fibromyalgia (FM) by US rheumatologists.

METHODS:
We assessed 1555 patients with FM with detailed outcome questionnaires during 11,006 semiannual observations for up to 11 years. At entry, all patients satisfied American College of Rheumatology preliminary 2010 FM criteria modified for survey research. We determined diagnosis status, rates of improvement, responder subgroups, and standardized mean differences (effect sizes) between start and study completion scores of global well-being, pain, sleep problems, and health related quality of life. (QOL)

RESULTS:
The 5-year improvement rates were pain 0.4 (95% CI 0.2, 0.5), fatigue 0.4 (95% CI 0.2, 0.05), and global 0.0 (95% CI -0.1, 0.1). The standardized mean differences were patient global 0.03 (95% CI -0.02, 0.08), pain 0.22 (95% CI 0.16, 0.28), sleep problems 0.20 (95% CI 0.14, 0.25), physical component summary of the Short-form 36 (SF-36) 0.11 (95% CI -0.14, -0.07), and SF-36 mental component summary 0.03 (95% CI -0.07, 0.02). Patients switched between criteria-positive and criteria-negative states, with 716 patients (44.0%) failing to meet criteria at least once during 4228.5 patient-years (7448 observations). About 10% of patients had substantial improvement and about 15% had moderate improvement of pain. Overall, FM severity worsened in 35.9% and pain in 38.6%.

CONCLUSION:
Although we found no average clinically meaningful improvement in symptom severity overall, 25% had at least moderate improvement of pain over time. The result that emerged from this longitudinal study was one of generally continuing high levels of self-reported symptoms and distress for most patients, but a slight trend toward improvement.

SOURCE: Abstract retrieved from PUBMED (PMID 21765102).

Full Text article was printed on July 15, 2011, doi: 10.3899/jrheum.110026.

To access the full article requires subscription to the Journal of Rheumatology. Physicians or interested parties can either subscribe to the print and/or online journal or use the "pay per article" option. 

 

 

 

 

Pharmacological therapies approved for FM

Fibromyalgia (FM) has received a lot more attention over the last couple of years through television and magazine advertisements promoting three new drugs indicated for use in FM. Lyrica (pregabalin), Cymbalta (duloxetine), and Savella (milnacipran) were approved by the Food Drug Administration (FDA) as effective treatments for FM based on their performance in clinical trials.

In order to meet the FDA criteria as "effective" treatments, these drugs had to show benefits or some measurable level of improvement in study participants as they compared to placebos (substances with no active ingredients) in each their own trials. These medications might provide considerable relief for some patients, but they do not work the same way for everyone with FM, for a number of reasons.

These particular drugs differ from each other in their chemical composition and modes of action (i.e., they target different brain chemicals). Therefore, how each patient responds to any one of these will greatly depend on his or her own body chemistry, variation in symptoms, and severity of illness. The majority of FM patients have pain and disrupted sleep, but some may find mood disturbances to be problematic, while others have digestive, intestinal or bowel sensitivities. It is not unusual for FM patients to be prescribed multiple medications, to manage multiple symptoms, which may put some patients at a greater risk of adverse drug interactions.

Whenever new treatments are being contemplated, the general rule is to select a drug where its benefits are thought to outweigh the potential risks, and anything else known about the patient's medical history that might negatively impact him or her. In addition, when starting out any new medication, it is usually recommended that individuals with FM begin with a very low dose (i.e. 25% of prescribed dose) and work their way up slowly to the full prescribed dose, watching for any adverse side effects. This particularly applies to these drugs.

Despite their limited "track records" there often tends to be an eagerness to try out the latest treatments. Decisions to initiate treatment are often based on favorable study results (i.e., the acceptance of study results at face value) and may not take into account other factors that influenced results (i.e., the severity of illness in the study participants or the placebo effect that produced favorable response). The result is the possibility of unrealistic expectations for the typical FM patient, who may have a more complicated history or combination of problems than study participants.

A group of German doctors conducted an extensive review of these three drugs on their overall efficacy, benefits and adverse effects, with one significant difference—they evaluated how they measured up to each other. Their comparative analysis was published in 2010 in the Journal of Pain, the official scientific journal of the American Pain Society. Their findings and excerpts from several other studies are examined later in this article. But first, we will review the basic properties of these medications and the developments since their release on the market.


Basics about medications approved for use in FM

Pregabalin (Lyrica)

The FDA approved Lyrica, made by Pfizer, Inc., in June 2007 as the first prescription medication for the treatment of FM. Very simply, Lyrica is thought to work by changing the effect of GABA (gamma amino butyric acid), often referred to as a "calming" neurotransmitter/brain chemical.

Structurally, it is related to Pfizer's first antiepileptic drug, gabapentin (Neurontin), which came on the market in 1983. Lyrica is found to be more potent and effective at lower doses than gabapentin (Neurontin). Its primary uses in FM are for pain relief and improvement of fatigue and sleep.

An "informal" review of several internet drug information sources show that patients' experiences with Lyrica varied widely, from stating that it caused many difficult side effects, rapid weight gain, and the drug was found to be very expensive, to praising it as the best treatment they've used to date. The average of the patient/user ratings placed Lyrica at slightly beyond the halfway point on the scale used. This information is meant to provide a general idea in how a random group of patients responded to this treatment—it is strictly subjective and not a medical interpretation.

Lyrica is also used to treat diabetic nerve pain, nerve pain after shingles and partial onset seizures in adults with epilepsy.

The most common side effects are weight gain, swelling of hands and feet, and may worsen "fibro fog" in some patients. In some clinical trials, dizziness and somnolence were the most frequently reported adverse events. Many of these side effects were echoed in the above-mentioned patient/user reviews.

It is important to report any unusual reactions to the prescribing physician, as some of these could be serious and warrant discontinuation of treatment—such as loss of coordination, uncontrolled movements, unusual fatigue, difficulty speaking or changes with vision.

Some patients have experienced depression, changes in their mood or have had suicidal thoughts. As a result, effective April 2009, Lyrica and Neurontin (along with other antiepileptic drugs) were required by the FDA to include a warning about the increased risk of suicidal thoughts or actions on their product labels.

Duloxetine (Cymbalta)

In June 2008, Cymbalta, manufactured by the Lilly Co., was approved by the FDA for use in FM, to help reduce pain and improve function. Cymbalta belongs to a class of medications called selective SNRIs (serotonin and norepinephrine reuptake inhibitors). It works by increasing the activity of these two neurotransmitters which are found to be deficient in FM.

By adjusting in how the brain and spinal cord respond to painful stimuli (which is part of the nociception system/how pain is sensed), is how it is thought to provide an analgesic effect.

Cymbalta is also indicated for the treatment of major depressive disorder, generalized anxiety disorder, management of diabetic peripheral neuropathic pain, and more recently, it was approved for the management of chronic musculoskeletal pain, including chronic osteoarthritis pain and chronic low back pain.

Though Cymbalta is suggested for a wide range of problems, it still should be approached as a potent treatment with a dual mechanism. A thorough assessment should be made of the patient's personal and/or family history of psychiatric problems (e.g. bipolar/manic-depressive disorders) as this drug may worsen or uncover these.

It is also very important to review all medications used by the patients (including over-the-counter products and supplements) in order to prevent serious interactions since one-fourth of all prescribed medications are metabolized by the same enzyme (CYP2D6).

These medications include other selective serotonin reuptake inhibitors (SSRI's), tricylic antidepressants (TCA's), beta-blockers, opiates, antiarrhythmics, migraine headache treatments, and various plant substances.

For their own safety, patients need to communicate with their doctors in an honest, open manner, and not withhold any information about what else they might be using on their own (including alcohol), and use medications exactly as prescribed.

In the event of adverse effects, patients need to inform their doctors about these problems and not make changes on their own.

NCBI warning for medication-induced suicidal tendencies. The National Center for Biotechnology Information (NCBI, a branch of the National Institutes of Health (NIH)) has posted an important warning about the potential risk of suicidal tendencies in some patients while using certain antidepressants, including, but not limited to, duloxetine (Cymbalta).

The NCBI advises that "all" patients should be informed about this risk and the early signs/symptoms associated with this risk. Family members or caregivers should know the same, so they can recognize warning signs. The reason for extra precautions, according to NCBI, is because people's mental health can change unexpectedly, even in individuals who do not have mental illness, but are using duloxetine to treat other conditions. This appears to happen, more often, at the beginning of treatment and/or when the dose is increased or decreased; therefore, their recommendation is that patients be closely monitored during these times. NCBI lists the following symptoms as potential warning signs of suicidal tendencies which need to be immediately reported to the doctor: "new or worsening depression; thinking about harming or killing yourself, or planning or trying to do so; extreme worry; agitation; panic attacks; difficulty falling asleep or staying asleep; aggressive or hostile behavior; irritability; acting without thinking; severe restlessness; frenzied abnormal excitement; or any other unusual changes in behavior."

Milnacipran (Savella) 

Savella was approved by the FDA in January 2009 as yet another FM-appropriate treatment. It is made by Forest Laboratories Inc., and falls into the same class of medications as Cymbalta.

However, its mechanism focuses on boosting norepinephrine levels more so than serotonin ones.

Its overall ability to reduce pain has been reported by several sources as being only "marginal."

Two of its more frequent side effects are increase in blood pressure and nausea.

According to the NCBI, milnacipran is currently not used in the U.S. to treat depression. The NCBI has issued the same warnings for milnacipran as for duloxetine regarding potential changes in mood and/or risk of suicidal thoughts and tendencies.


How do these medications compare to each other?

A group of German doctors retrieved and reviewed data from previous studies conducted for all three pharmacological therapies, totaling 17 studies and 7,739 patients who met the inclusion criteria. (Such a study is called a meta-analysis.)

Some of their sources included MEDLINE, SCOPUS, Cochrane Central Register of Controlled Trials, as well as unpublished data from FDA and NIH databases and others. Even though these studies may have some variations in how they were conducted, the amount of data reviewed was quite substantial.

(See our editorial note at the end of this article concerning the validity of meta-analyses such as this one.)

The article is written by Häuser W, et al, titled "Comparative efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrome", and was published in the Journal of Pain, 11 (2010): 505-521.

One of the most remarkable findings in their analysis of these medications and their ability to reduce pain was that "adjusted indirect comparisons indicated no significant differences for 30% pain relief." This suggests that none of these were found to be highly effective against pain and they all seemed to be about the same, when evaluating degree of pain relief.

When combining pain and sleep disturbances, duloxetine (Cymbalta) and pregabalin (Lyrica) were found to be considerably more effective than milnacipran (Savella).

Milnacipran (Savella) and pregabalin (Lyrica) were more beneficial in reducing fatigue than duloxetine (Cymbalta), while duloxetine had a stronger impact on mood.

Both SNRI's caused more headaches and nausea/digestive symptoms and also raised blood pressure.

This comparison of specific features of these medications may be very helpful in a clinical setting as physicians try to select the most suitable treatment for each individual patient.

Though the level of pain relief or other noted improvements can be modest, or even minimal in some cases, drugs can still meet approval by the FDA. As mentioned above, pharmaceutical companies only need to show that a drug performs better than a placebo.

For example, Medical News Today reports the following data on clinical trials testing Cymbalta's effectiveness for FM: "Lilly established the efficacy of Cymbalta in two pivotal three-month clinical trials involving 874 patients with fibromyalgia. In both studies, Cymbalta reduced pain at study endpoint compared with placebo as measured by the Brief Pain Inventory (BPI) ... improvement in pain for Cymbalta vs. placebo was observed in the first week of each study. Fifty-one percent and 55 percent of patients on Cymbalta had a 30 percent improvement on the BPI at endpoint (clinically meaningful relief is considered at least 30 percent pain reduction)."

Some physicians are not convinced that all new drugs are better just because they are new, generally speaking, since this applies to treatments indicated for other conditions. The reason for their doubts is that the effectiveness/benefits of new drugs are not often compared to existing drugs.

In one unusual case, clinical trials for a new drug that was supposed to be promoted as another treatment for FM were abruptly terminated by Pfizer in February 2009. The "Musculoskeletal Report" (a source for Biopharm business news) announced that Pfizer had re-evaluated this drug, esreboxetine, and concluded its potential benefits to FM patients would not be too substantial.

The President and General Manager of Pfizer's Primary Care Business Unit, Pedro Lichtinger issued this statement, "While confident in the safety of these compounds, we don't believe that they provide significant benefit over other therapies."

Esreboxetine was a selective norepinephrine reuptake inhibitor that Pfizer, Inc. was working on for use in FM. It is thought to be essentially the same drug as reboxetine (Edronax), also made by Pfizer, but currently approved as a treatment for depression.

Though one can only speculate about the potential value this drug might have had for FM (or not), it becomes all the more evident that "head to head" trials (i.e., studies in which one drug is directly compared to another drug or drugs from the same class or group) might be the best way to demonstrate the advantage of one treatment over another.

Reference

Häuser W et al, "Comparative efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrom," Journal of Pain 11, no. 6 (2010): 505-521. 


Editorial comment on Statistical Meta-analysis

The Massachusetts CFIDS/ME and FM Association would like to bring to the attention of our readers that the type of study conducted by the group of German doctors discussed in this article is referred to as a "meta-analysis." This term refers to the statistical analysis of a group of individual studies.

The authors of a meta-analysis re-analyze the results of many smaller studies (with only the limited information available in each published report of a study, not the original data from each) pooled as if a larger study had been done with all of the patients in the smaller studies.

Thus a meta-analysis will take results from 10 studies of 10 patients each and claim to have valid results from 100 patients, but without having access to the original data for each of the 100 patients.

Thus a meta-analysis, in itself, is not an actual scientific study, but a type of averaging of averages from many different studies.

Therefore, from a mathematical and also a medical standpoint, trying to get "effectiveness" data comparing drugs from varying studies that only compared a single drug to placebo is not really valid. There are too many factors that can throw one's conclusions off such as variations in study length, severity of FM in patients of different studies, numbers of dropouts in a study due to severity of side-effects, etc.

So the German meta-analysis is similar to comparing apples to oranges (placebo), persimmons to oranges and redwood trees to oranges, and then coming up with conclusions about how apples, persimmons and redwood trees compare to each other.

On the other hand, the German meta-analysis provides a broad review of a large number of studies. It is worth considering its conclusions, but they really shouldn't be taken as "gospel."

To put things even more into perspective, some time ago a meta-analysis of treatments for CFS found that Cognitive Behavioral Therapy (CBT) was the "best" treatment for CFS.

The facts that most of the studies analyzed used the Oxford definition of CFS and compared CBT to placebo, and only a few of the analyzed studies looked at other treatments and patients identified by the 1988 or 1994 definitions of CFS, were ignored.

Thus, the conclusion of a meta-analysis can be heavily influenced by the number of studies of a certain treatment outweighing the number of studies looked at in the analysis that used a different treatment. We don't know if that is the case in this German study, but it could be.

2010 Study Finds That Pain Levels in Patients With Fibromyalgia Are Linked to Resting Brain Connectivity

A study published in the August 2010 Arthritis & Rheumatism by Vitaly Napadow, Ph.D. and colleagues has shown that patients with fibromyalgia (FM) have a different degree of connectivity between specific brain networks as compared with healthy controls.

The study, entitled “Intrinsic Brain Connectivity in Fibromyalgia Is Associated With Chronic Pain Intensity,” also demonstrated a relationship between the activity in these brain networks and perceived levels of spontaneous pain in those with FM.

Functional magnetic resonance imaging (FMRI) was used to gather information about the resting brain activity in 18 female patients with FM and 18 female age-matched healthy control subjects between the ages of 18 and 75. Subjects were first asked to rate the degree of pain they were in just prior to the FMRI and then “to rest comfortably without falling asleep” while FMRI data was gathered.

The researchers chose to examine the resting state of the brain because they were looking for neural correlates of the chronic endogenous pain or “spontaneous pain” that is characteristic of FM as opposed to the hypersensitivity that FM patients exhibit to external sources of pain (also known as hyperalgesia).

Therefore, the researchers measured intrinsic brain connectivity which is the basic “ongoing neural and metabolic activity” that occurs while the brain is at rest and not responding to stimuli.

The researchers hypothesized that FM patients would have an altered level of resting-state connectivity in the default mode network (DMN) and the executive attention network (EAN) while the connectivity of the medial visual network (MVN) would be comparable to that in healthy controls. The DMN and EAN are both involved in cognitive processes that can be impaired in those with FM.

The DMN is believed to be involved in self-referential thinking and is comprised of brain regions that have been shown to be deactivated by experimental pain, while the EAN is involved in working memory and attention.

Conversely, the MVN is made up of the primary visual processing areas that are not known to be affected by FM. Thus, the MVN served as a negative control.

The researchers also controlled for age (as age and spontaneous pain were significantly positively correlated) and for physiological factors such as cardiorespiratory fluctuations, which can affect FMRI measurements of intrinsic connectivity.

In keeping with the given hypothesis, patients with FM exhibited greater DMN and EAN (specifically the right half of the EAN) connectivity than healthy controls.

As predicted, there was no significant difference between the MVN connectivity levels in the FM patients and healthy controls. Patients with FM had a higher intrinsic DMN connectivity to other parts of the brain that are involved in pain processing such as the left anterior, middle, and posterior insula.

Meanwhile, the FMRI results showed that these same patients also had greater intranetwork connectivity within the right EAN.

Additionally, the researchers found that increased levels of connectivity between both the DMN and the right EAN and the insula were positively correlated with higher patient-reported pain levels.

These neural disparities between FM patients and healthy controls could serve as biomarkers that in turn could aid in diagnosis, help to validate chronic pain symptoms, and further our understanding of the physiological basis for these symptoms.

For instance, the researchers speculated that the increased connectivity between the insula and the EAN during increased subjective feelings of pain could be causing interruption of the normal functions of the EAN (working memory and attention), which could help to explain some of the cognitive deficits (also known as “fibro fog”) experienced by patients with FM.

Moreover, the abnormal functioning of these brain networks adds credence to the burgeoning theory that spontaneous pain associated with FM may be more closely linked to central nervous system hyperexcitability than to pathology of the nerves outside of the brain and spinal cord.

Interestingly, the authors, in this small study, attempted to separate out the potential overlap of depression with the pain associated with FM:

“In order to test for the influence of depression on any of our pain-related results, we also evaluated whether patients with FM classified as having a high level of depression…had greater ICN connectivity in any of the regions implicated…Based on our criteria, 7 patients had a high level of depression, while the remaining 11 patients were classified as having a low level of depression. We found no significant differences (all P>0.2) between these two FM subpopulations…in terms of ICN connectivity to regions of interest…Of particular interest, cognitive deficits in patients with FM are correlated more with their level of pain than with psychiatric comorbidities (e.g., depression, anxiety, or sleep disruption)…”

The importance of this study is summed up by the authors:

“In this study, we present the first direct evidence between elevated intrinsic brain connectivity and spontaneous pain intensity in patients with FM…Furthermore, our data directly link ratings of self-reported spontaneous pain at the time of the scan to the degree of both right EAN and DMN connectivity to the insula. Our findings have implications for a better understanding of the underlying brain mechanisms of endogenous clinical pain in FM, potentially pointing toward biomarkers of disease progression…”

For those wishing to read the full study, it can be obtained by a link on the Abstract page: http://www.ncbi.nlm.nih.gov/pubmed/20506181

Books about Fibromyalgia

The Massachusetts CFIDS/ME & FM Association does not assume any responsibility for the outcome of treatments or other self-care strategies described in any of the listed books, that might be undertaken by readers and we recommend individuals always consult with their healthcare providers before trying any new treatment, supplement, or healthcare product.

Fibromyalgia

Fibromyalgia for Dummies, by Dr. Roland Staud, 2007, ISBN:  0764554417

Despite the trend of having a "Dummies" book for just about anything imaginable and leaving the impression the topic might be lightly treated, that is not the case with this relatively new book on FM. The author is Dr. Roland Staud, a well-known rheumatologist who specializes in FM, conducts research on FM at University of Florida, and contributes articles for leading FM newsletters. Dr. Staud provides accurate and current information about FM and reviews numerous treatment interventions and other aspects with an open mind. It may have a slight drawback, that as a "Dummies" book, the material may viewed by some as a little bit simplified. However, we still rate this as one of the better new books on FM. It will likely meet the needs of newly diagnosed patients with FM and their family members as well as patients who would like to update their home library.

Fibromyalgia and Chronic Myofascial Pain: A Survival Manual, by Devin Starlanyl, 1996, ISBN: 1572240466

Fibromyalgia and Chronic Myofascial Pain: A Survival Manual (2nd Edition), by Devin Starlanyl, 2001, ISBN: 1572242388

The Fibromyalgia Advocate, by Devin Starlanyl, 1999, ISBN: 1572241217

An overview of this trio of books, written by Devin Starlanyl, is being provided concurrently because of her unique style and unique format of these books. The books are larger than most (about the size of phone book) and are finished with the same, signature design on the cover—they are very easy to spot. The original edition (1996) of the "survival manual" was one of the most welcomed, patient guides to hit bookshelves—often referred to as the "big blue Bible" on FM. Five years later, an updated version (with a jade green cover) was released to include more recent information on research, medications, and special issues.

The overall appeal of Starlanyl's books is not only detail which she goes into, great coping tips and advice given, but also the handy worksheets and numerous sketched figures with illustrated trigger points which are included in the manuals. These illustrations help to show where many symptoms may originate from (much of this information, she writes, was based on Drs. Travell's and Simons' publications on myofascial pain).  Few books cover these coexisting conditions and explain perpetuating factors to this level.

Devin Starlanyl has been long involved with patients by starting one of the first FM/MPS internet groups, lecturing about the illnesses, and as a physician, also treating patients with the same. She is also someone who has both illnesses herself and thus, she is able to write and communicate with a deep personal appreciation of FM and MPS. The book on advocacy (with the bright purple cover) is pretty much what the name suggests—it is a resource manual with advice on how to deal with many situations, like legal rights, disability, other special issues and includes "data sheets" with references which patients can copy and take with them on doctors' appointments. These books are very informative and practical—one might very likely find the original edition at public libraries, but the 2nd edition would make for a good investment by anyone with FM.

Coury, F. et al., "Rheumatoid Arthritis and Fibromyalgia: A Frequent Unrelated Association Complicating Disease Management"

Coury, F. et al., "Rheumatoid Arthritis and Fibromyalgia: A Frequent Unrelated Association Complicating Disease Management," J. Rheumatol. Dec 15 (2008). [Epub ahead of print] PMID: 19132794

Objective. To assess the value of the 28-joint Disease Activity Score (DAS28) in evaluating disease activity in rheumatoid arthritis (RA) associated with fibromyalgia (FM). In this situation, because of the weight of the subjective measures included in the DAS28 equation, the patient's status may be overestimated, leading to inappropriate treatment. We analyze the relationship between RA and FM and discuss whether the association is random or a marker of poor prognosis.

Methods. A questionnaire, developed when biologic therapies were introduced, was administered and the results analyzed in a consecutive, female outpatient population including 105 patients with RA, 49 with RA and FM (RAF), and 28 with FM. Psychosocial characteristics, disease presentation, and radiographic joint destruction evaluation were compared in the 3 populations.

Results. The presentation of RA was the same in patients with RA and RAF, but the 2 populations differed by socio-professional characteristics, significantly higher disease activity in patients with RAF, and significantly more severe joint destruction in patients with RA. The RAF group was similar to the FM control population in socio-professional and some physical characteristics. Regression analysis using the DAS28 measures differed significantly in the weight allowed to 28-joint counts for pain and swelling, but the constant factor was higher in patients with RAF.

Conclusion. DAS28 overestimated objective RA severity in patients who also had FM. The association between RA and FM does not appear to be a marker of worse prognosis, but rather a fortuitous association between the 2 diseases and one that may afford these patients some protection against joint destruction.