More evidence for an immune/inflammatory imbalance in both bipolar disorder and teenage suicide

Posted on December 19, 2011 by Dr. Jonathan

Summary: Neuroinflammatory signaling molecules are elevated in bipolar disorder patients compared to controls. Marked increases in proinflammatory cytokines are also observed in the brains of teen suicide victims. Brain inflammation, immune system dysregulation and the loss of self-tolerance are key factors in the management of BP and major depression.

A paper just published in the Journal of Psychiatric Research offers further evidence for the role of neuroinflammation resulting from immune system dysregulation in bipolar disorder. The authors state:

“Bipolar disorder (BD) is associated with considerable higher chronic medical comorbidities, overweight and obesity. Adipokines are adipocyte-derived secretory factors which have functions in immune response and seem to be associated with both BD and overweight. The aim of this study was to evaluate the plasma levels of adipokines (adiponectin, resistin and leptin) and TNF-α and its receptors (sTNFR1 and sTNFR2) in BD overweight patients in comparison with overweight controls.”

The authors measured plasma levels of adiponectin, resistin, leptin, TNF-α and TNF-α soluble receptors in thirty bipolar patients along with thirty controls matched by age, gender and body-mass index (BMI). The subjects were also assessed by Mini-International Neuropsychiatric Interview, Young Mania and Hamilton Depression rating scales. What did the data show?

“BD patients presented increased plasma levels of adiponectin, leptin and sTNFR1.”

This is but one drop in a sea of emerging evidence for the role of brain inflammation and immune dysregulation in neuropsychiatric disorders that clinicians should consider in comprehensive case management. The authors conclude:

“This study provides further support to the hypothesis of the immune/inflammatory imbalance in BD.”

Another study in the same journal documents a marked increase in proinflammatory cytokines in the frontal lobes of teenagers attempting suicide. The authors observe:

“”Proinflammatory cytokines play an important role in stress and in the pathophysiology of depression—two major risk factors for suicide. Cytokines are increased in the serum of patients with depression and suicidal behavior; however, it is not clear if similar abnormality in cytokines occurs in brains of suicide victims.”

So they evaluated 24 teenage suicide victims and 24 matched normal control subjects for gene and protein expression levels of the proinflammatory cytokines interleukin (IL)-1β, IL-6, and tissue necrosis factor (TNF)-α in the prefrontal cortex (PFC). Again we see the markers for brain inflammation:

“Our results show that the mRNA and protein expression levels of IL-1β, IL-6, and TNF-α were significantly increased in Brodmann area 10 (BA-10) of suicide victims compared with normal control subjects.”

This is the deepest biological expression of the loss of self-tolerance in these disorders. Autoimmune inflammatory conditions require evaluation of all the known underlying causal factors that may contribute to the loss of self and chemical tolerance in order to design the most helpful treatment plan. The authors conclude:

“These results suggest an important role for IL-1β, IL-6, and TNF-α in the pathophysiology of suicidal behavior and that proinflammatory cytokines may be an appropriate target for developing therapeutic agents.”

Apple polyphenols each day may help keep intestinal inflammation away

Posted on December 19, 2011 by Dr. Jonathan

Summary: phenolic compounds in apples have beneficial effects for autoimmune inflammatory bowel disease.

A paper just published in the Journal of Leukocyte Biology demonstrates the mechanism by which polyphenols in apples help quell the inflammation of the autoimmune diseases ulcerative colitis and Crohn’s disease. The authors state:

“Human IBD, including UC and Crohn’s disease, is characterized by a chronic, relapsing, and remitting condition that exhibits various features of immunological inflammation and affects at least one/1000 people in Western countries. Polyphenol extracts from a variety of plants have been shown to have immunomodulatory and anti-inflammatory effects. In this study, treatment with APP [apple polyphenols] was investigated to ameliorate chemically induced colitis.”

The authors administered APP to study animals genetically predisposed to autoimmune inflammatory bowel disease win whom inflammation as induced by chemical irritation. Their findings documented an protective effect:

“Oral but not peritoneal administration of APP during colitis induction significantly protected C57BL/6 mice against disease, as evidenced by the lack of weight loss, colonic inflammation, and shortening of the colon. APP administration dampened the mRNA expression of IL-1β, TNF-α, IL-6, IL-17, IL-22, CXCL9, CXCL10, CXCL11, and IFN-γ in the colons of mice with colitis.”

A rational treatment strategy for autoimmune disease requires an assessment of the factors involved in the loss of self-tolerance, including integrity of barrier systems, glutathione production and recycling, nitric oxide synthase production, regulatory T cell function, cytokine regulation, antigenic environmental triggering agents, lifestyle factors that modulate genetic expression, etc. For palliation, however, interventions that can reduce inflammation without side effects are desirable. Although an extract concentrates polyphenols more than is obtained by eating apples, compounds like this and resveratrol are worthy of consideration for adjunctive use. The authors conclude:

“…these results show that oral administration of APP protects against experimental colitis and diminishes proinflammatory cytokine expression via T cells.”

Depression as a dysfunction of the immune system

Posted on December 7, 2011 by Dr. Jonathan

Summary: chronic inflammation due to immune system dysregulation, with or without a diagnosed autoimmune disease, plays a fundamental role in chronic depression. This offers sustainable and evidence-based treatments for depression and brain health.

The authors of an important paper published in Current Immunology Reviews state:

…current antidepressants do not effectively target all of the pathological processes that are responsible for the major symptoms of depression…However, in recent years greater attention has been directed to the inter-relationship between the brain and peripheral organs (the” body-mind” connection) in which changes in the endocrine and immune systems play a major role in the pathological changes that occur in depression. Thus inflammation is beginning to emerge as a major contributing factor not only to depression and other major psychiatric disorders…”

Two major ways that immune dysfunction promotes depression are emphasized: the direct effect of inflammation on the brain, and the brain effects of the hormonal response to inflammation. Regarding the former:

“…in the past 30 years or so that clinical and experimental evidence has been obtained clearly demonstrating that aspects of both cellular and humoral immunity were dysfunctional in major depression…in particular the pro- and anti-inflammatory cytokines…Such clinical observations suggest that proinflammatory cytokines contribute to the major symptoms of depression and now forms the basis of the inflammation, cytokine or inflammatory response hypothesis of depression.”

It’s now known that peripherally derived inflammatory cytokines have access to the brain, including areas involved in depression…

“Once in the brain, the proinflammatory cytokines activated both neuronal and non-neuronal (for example, the microglia, astrocytes and oligodendroglia) cells via the nuclear factor-kappa-beta (NF-kB) cascade in a similar manner to that occurring in the peripheral inflammatory response…

Also, the production of serotonin and dopamine is adversely affected by inflammation:

“Recently much attention has been paid to the activation of the tryptophan-kynurenine pathway by these cytokines whereby tryptophan is shunted from the synthesis of serotonin to that of kynurenine…clearly this is an important mechanism whereby serotonergic function is decreased in depression. The activity of the dopaminergic system is also reduced in response to inflammation. For example, IFN reduces the synthesis of dopamine by decreasing the concentration of the co-factor tetrahydrobiopterin (BH4)…As IFN increases the synthesis of nitric oxide by activating the BH4 dependent enzyme nitric oxide synthase in the microglia it seems likely that the reduction in dopaminergic function is linked to the increase in nitric oxide. This gaseous neurotransmitter is known to activate the glutamatergic system which, when this exceeds physiologically limits, enhances apoptosis and neurodegeneration.”

In other words, an increase in inflammatory cytokines derails the production of serotonin and dopamine, and activates the excitatory (glutamatergic) system to the point of cell death.

Additionally, proinflammatory cytokines activate the HPA (hypothalamo-pituitary-adrenal) axis causing excessive cortisol production which is lethal to brain cells at high levels…

“In addition to the modulation of neurotransmitter function, proinflammatory cytokines contribute to the major symptoms of depression by activating the HPA axis by increasing the release of CRF, thereby contributing to hypercortisolaemia, a feature of major depression. The mechanism whereby the cytokines induce hypercortisolaemia involves a decreased sensitivity of the glucocorticoid receptors thereby leading to glucocorticoid resistance…”

The inflammation model also sheds light on the role of stress in depression:

“…as major depression is often accompanied by inflammatory diseases (such as irritable bowel syndrome, type 2 diabetes, arthritis and autoimmune disorders) that can activate the peripheral and central inflammatory response, it is possible that such inflammatory disorders initiate the inflammatory changes that precipitate depression….[But] it is evident that inflammation also occurs in depressed patients who are not suffering from concurrent inflammatory disorders. Thus the increased vulnerability of depressed patients to psychosocial stress is probably the key factor that leads to the activation of the immune and endocrine axes in depression. It is known, for example, that even the relatively mild acute stress of public speaking causes an increase in NF-kB activity, a key element in the induction of the inflammatory cascade. In this regard, it is also known that patients with major depression frequently show an enhanced responsiveness of IL-6 and NF-kB to an antigen challenge…such changes appear to be associated with activation of the microglia thereby suggestion that the inflammatory changes are also occurring in the brain.”

In other words, patients with major depression have a more pronounced inflammatory response to substances to which they are sensitized or allergic to (antigens). This is in addition to an increased immune and hormonal response to psychosocial stress.

Of special significance for the use of heart rate variability analysis for evaluation of the autonomic nervous system and therapies that increase parasympathetic tone…

“The mechanism whereby psychological stress influences both the peripheral and central inflammatory cascade is co-ordinated by the autonomic nervous system. Thus the release of noradrenaline and adrenaline following the activation of the sympathetic system results in the activation of both alpha and beta adrenoceptors on immune cells thereby initiating the release of proinflammatory cytokines, via the activation of the NF-kB cascade, particularly on macrophages and monocytes in peripheral blood…Conversely stimulation of the parasympathetic system has the opposite effect on the stress induced inflammatory response…It is possible that the anti-depressant-like action of vagal nerve stimulation, occasionally used to treat resistant depression, is associated with such an anti-inflammatory action.”

Brain inflammation associated with depression actually causes the death of brain cells (apoptosis):

“Thus in major depression, the prolonged activation of the inflammatory network in the brain results in a decrease in neurotrophins, leading to reduced neuronal repair, a decrease in neurogenesis, and an increased activation of the glutamatergic pathway that contributes to neuronal apoptosis, oxidative stress and the induction of apoptosis in astrocytes and oligodendrocytes.”

On top of all this, inflammation causes the biochemical pathway that produces serotonin from tryptophan to converted to the production of neurotoxins instead through the tryptophan-kynurenine pathway and the production of quinolinic acid.

“As both the cytokines and cortisol are raised in major depression, it is not surprising to find that the tryptophan-kynurenine pathway is increased….Kynurenine hydroxylase metabolises kynurenine first to 3-hydroxykynurenine and then to 3-hydroxyanthranilic acid and quinolinic acid. This pathway is increased in depression and dementia…In chronic depression…the activated microglia produce an excess of the neurotoxin…Furthermore quinolinic acid can cause apoptosis of the astrocytes. This results in a reduction in the metabolic and physical buffer to the neurons that is usually provided by the astrocytes and thereby further exposes the neurons to the neurodegenerative actions of quinolinic acid.”

Inflammation in the brain over the long term causes neurodegeneration that appear as brain shrinkage:

“The structural changes observed in the brain of patients with chronic depression lends support to the neurodegenerative hypothesis of depression. It is known that there is a shrinkage of the hippocampus in patients with major depression and a decrease in the number of astrocytes and a neuronal loss in the prefrontal cortex and in the striatum. Such changes could be the consequence of chronic low grade inflammation in which the proinflammatory cytokines, nitric oxide, prostaglandin E2 and other inflammatory mediators play key roles; the cytokines are known to induce the cyclo-oxygenase and nitric oxide sythase pathways in the brain and thereby increase the inflammatory insult. The inhibition of neurotrophin synthesis in the brain by glucocorticoids, and the neurotoxic action of quinolinic acid, add further to the impact of the inflammatory changes.”

There are indications that patients who respond poorly to neurotransmitter-manipulating medications have markers for increased inflammation:

“Further evidence for the relationship between inflammation and depression is provided by the observation that depressed patients with a history of partial or lack of response to antidepressant treatments have elevated plasma concentrations of IL-6 and acute phase proteins that persist despite antidepressant treatment. It has been suggested that patients who are resistant to conventional antidepressant treatment possess abnormal alleles of the IL-1 and TNF genes, and possibly for T-cell function.”

Moreover, even when there is some relief from a depressed mood or anxiety with these medications…

“…there is abundant clinical evidence that the available antidepressants…are far less effective in treating the memory and cognitive dysfunction (fatigue, psychomotor retardation) that commonly affect middle aged and elderly depressed patients.”

There is mounting evidence that modulating inflammation can improve the inflammatory response:

“There are already indications from the clinical literature that TNF antagonists…reduce the symptoms of depression in a variety of patients with autoimmune diseases…the mood state of the patients improving before the signs of improvement of the autoimmune disorder…IL-10, and insulin-like growth factor that has prominent anti-inflammatory activity, have been shown to attenuate the depressive-like behaviour in rodents induced by an inflammatory challenge.”

IL-10 is increased by correcting suboptimal levels of vitamin D.

“Perhaps the most obvious step to the reduction of inflammation both centrally and peripherally is to reduce the activity of the prostenoid pathway and thereby reduce the synthesis of inflammatory prostaglandins such as PGE2.”

This is exactly what is accomplished by correcting an omega-3 fatty acid deficiency with a low 3:6 ratio.

The best chance for a sustainable program for helping depression by treating the inflammation is to determine with the appropriate tests why the excessive inflammation is happening in the first place. Then physiological and sustainable treatments can address those underlying causes properly. That brings up the very large topic of the functional management of autoimmune disease and chronic inflammation, a subject of many posts here and deserving of a weighty textbook. See posts forthcoming in the next week on the role of gastrointestinal inflammation as a contributing cause and treatment target for depression and the effectiveness of the omega-3 fatty acid EPA as a PGE2 reducer for depression.

Patients with psoriasis are at increased risk for vascular disease

Posted on November 25, 2011 by Dr. Jonathan

Summary: People with psoriasis are at increased risk for vascular disease. They require more aggressive screening and treatment.

A study published in the Journal of General Internal Medicine alerts us to pay special attention to vascular risk factors for those with psoriasis.The authors note:

“Psoriasis afflicts 2-3% of the world’s population. Affected patients commonly have risk factors for cardiovascular disease (CVD). In addition, psoriasis is independently associated with CVD and mortality.”

They set out to…

“…determine which CVD risk factors are associated with psoriasis independent of confounders, whether psoriasis is associated with CVD independent of CVD risk factors, and whether there is increased mortality among patients with psoriasis.”

90 studies out of 2,303 met the inclusion criteria for the authors’ review. The data led to this conclusion:

“Patients with psoriasis demonstrate a higher prevalence of cardiovascular risk factors and appear to be at increased risk for ischemic heart disease, cerebrovascular disease, and peripheral arterial disease. This increase in vascular disease may be independent of shared risk factors and may contribute to the increase in all-cause mortality….Physicians should screen for and aggressively treat modifiable risk factors for CVD in patients with psoriasis.”

These findings are not surprising considering the fundamental role of inflammation and autoimmune component of cardiovascular disease. Searching earlier posts for cardiovascular disease (search box above) will yield further evidence on this topic.

Helicobacter pylori infection and autoimmune diseases

Posted on September 25, 2011 by Dr. Jonathan

Those managing cases of Helicobacter pylori infection (according to the World Health Organization the most common infection worldwide) should be alert to the association of Helicobacter infection and autoimmune diseases. The authors of a paper published in the journal Biomedicine & Pharmacotherapy discuss this connection, beginning with the autoimmune component of cardiovascular disease:

“In the last few years several studies have been performed on the association between H. pylori infection and a miscellany of extragastric disorders which also include autoimmune diseases. In particular, emerging evidence seems to give a potential role for H. pylori in ischaemic heart disease via a cross mimicry between antibodies against heat shock protein 65 which are produced in the consequence of infection, but which are also expressed in atherosclerotic lesions.”

They note that other autoimmune diseases have been recognized in this regard:

“In cases of healing of Sjogren syndrome and Schonlein-Henoch purpura have also been reported. A recent study, moreover, showed that eradication of H. pylori infection may be effective in the disappearance of autoimmune thrombocytopenia. Finally, a role for H. pylori has also been postulated in other autoimmune diseases such as membranous nephropathy and some acute immune polyneuropathies.”

We can also appreciate a paper just published in the journal Oral Diseases in which the authors observe:

“Helicobacter pylori (H. pylori) is a widely prevalent microbe, with between 50 and 80% of the population infected worldwide. Clinically, infection with H. pylori is commonly associated with peptic ulcer disease, but many of those infected remain asymptomatic.”

They proceed to elaborate on the implications for autoimmune disorders:

“H. pylori has evolved a number of means to affect the host immune response and has been implicated in many diseases mitigated by immune dysregulation, such as immune thrombocytopenic purpura (ITP), atrophic gastritis, and mucosa associated lymphoid tissue (MALT) lymphoma. Autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren’s syndrome, are the result of a dysregulated host immune system which targets otherwise healthy tissues…Because of its prevalence and ability to affect human immune function, many researchers have hypothesized that H. pylori might contribute to the development of autoimmune diseases. In this article, we review the available literature regarding the role of chronic H. pylori infection in various autoimmune disease states.”

Case management of H. pylori infection requires vigilance for the possibility of an autoimmune condition, and for those suffering an autoimmune diagnosis the possibility of infection should be ruled out.

Sjögren syndrome and autoimmune thyroiditis

Posted on September 22, 2011 by Dr. Jonathan

Although autoimmune diseases are labeled as separate diagnostic entities, it’s important to bear in mind that this nomenclature masks the fact that they are like branches growing from the same trunk. While the tissue targets of autoimmune inflammatory attack differ according to the individual, the underlying causal factors are similar. Moreover, if one tissue is under autoimmune attack, it is almost always that others are too. A report published in the Journal of Clinical Rheumatology draws attention to the association of autoimmune thyroid disease and Sjögren syndrome. The authors state:

“The thyroid, salivary, and lacrimal glands are susceptible to immunologic damage, which can be expressed as an organ-specific autoimmune disease such as thyroiditis, or a systemic autoimmune disease such as primary Sjögren syndrome (pSS). Sjögren syndrome is characterized by the progressive destruction of the exocrine parotid and lacrimal glands, causing mucosal and conjunctival dryness (sicca syndrome). The serology of patients with pSS often shows elevated levels of antibodies including antinuclear antibody, rheumatoid factor, Ro (SS-A), and La (SS-B). There is a growing body of literature suggesting an increased risk of autoimmune thyroid disease (AITD) in individuals with pSS and an increased risk of pSS in individuals with AITD.”

They continue to describe the case of a 41-year-old man suffering from autoimmune hypothyroid disease who was also found to have pSS after thyroid hormone replacement therapy was initiated. They elaborate the salient implications:

“Patients with one autoimmune disease are often at increased risk for developing another autoimmune disease. In the case of 170 Hungarian subjects with Hashimoto thyroiditis (HT), 17% had Sjögren syndrome. In a group of 176 Spanish patients with AITD…the prevalence of keratoconjunctivitis was 23% and that of xerostomia was 37%. In 2 smaller studies of patients with autoimmune thyroiditis and hypothyroidism, 22% to 58% had salivary gland abnormalities as demonstrated by parotid scintigraphy, sialometry, and/or salivary gland biopsies showing lymphocytic involvement.”

Furthermore…

“…patients with pSS may show higher rates of AITD. The largest retrospective study to date included 479 patients from Hungary with pSS, who had thyroid function testing every 3 to 6 months. The frequency of HT was 6%, which was greater than the 1% to 2% frequency in the general population…In other smaller studies, the prevalence of HT in patients with pSS ranged from 11% to 50%.”

The authors note a study in which the sera from 26 patients with pSS and 7 patients with hypothyroid were tested for antihuman thyroglobulin (antihTg) antibody activity. Interestingly, all of the pSS sera contained IgG and IgM antihTg autoantibodies, the antihTg autoantibodies in patients with pSS and HT overlapped in their reaction with a certain region on the thyroglobulin molecule. They conclude:

“As demonstrated in this case, primary Sjögren syndrome and AITD are often associated. Although not all studies consistently demonstrated an increased association, the number of positive studies and the larger studies suggest a true association…Rheumatologists and endocrinologists may miss the presence and association of these 2 autoimmune conditions, given several nonspecific and overlapping symptoms such as fatigue, weight gain, and diffuse myalgias. We therefore recommend that rheumatologists consider assessing patients with Sjögren syndrome with periodic thyroid function testing.”

Moreover, clinicians managing any autoimmune disease should be alert to the presence of autoimmune activity involving additional target sites. And of course we must bear in mind the necessity of going beyond symptom management to investigate and treat the underlying causal factors. Those with a particular interest may wish to read the earlier post on Sjögren syndrome.

Sjögren’s syndrome—what more can we do?

Posted on June 26, 2011 by Dr. Jonathan

Our understanding of the autoimmune basis of Sjögren’s syndrome has evolved in the past several years, and this is offering new considerations for rational therapy that go beyond the old standard of care with its disappointing results. The authors of a paper recently published in the journal Arthritis Research & Therapy state:

“In vitro and in vivo experimental data have pointed to new immunopathogenic mechanisms in primary Sjögren’s syndrome (pSS). The availability of targeted treatment modalities has opened new ways to selectively target these mechanistic pathways in vivo. This has taught us that the role of proinflammatory cytokines, in particular TNFα, is not crucial in the immunopathogenesis of pSS. B cells appear to play a major role, as depletion of B cells leads to restoration of salivary flow and is efficacious for treatment of extraglandular manifestations and mucosa-associated lymphoid tissue lymphoma. B cells also orchestrate T-cell infiltration and ductal epithelial dearrangement in the salivary glands. Gene profiling of salivary gland tissue in relation to B-cell depletion confirms that the axis of IFNα, B-cell activating factor, B-cell activation, proliferation and survival constitutes a major pathogenic route in pSS.”

B cells are a kind of white blood cell (lymphocyte) that, when stimulated by an antigen, turn into plasma cells that produce antibodies that further attack that antigen. This is part of the humoral (versus cell-mediated) or Th2 (versus Th1) immune response. In addition to interferon alpha (IFNα) and B-cell activating factor, a study published in Clinical Immunology details the role of interleukin-14 alpha (IL-14a) in Sjögren’s syndrome. The authors state:

“To evaluate the role of interleukin 14 alpha (IL-14a) in Sjögren’s syndrome (SS), we evaluated the expression of IL-14a in the peripheral blood lymphocytes (PBL) of patients with primary and secondary SS and normal controls by quantitative RT-PCR.”

They concomitantly examined transgenic IL-14a mice for both tissue and immune characteristics of Sjögren’s syndrome. Interestingly…

“Patients with both primary and secondary Sjögren’s syndrome expressed IL-14a at statistically higher levels in their peripheral blood compared to normal controls matched for age, sex and ethnic group. Transgenic mice in which IL-14a expression was increased constitutively were previously demonstrated to develop…all the clinical and immunological features of primary Sjögren’s disease…Thus IL-14a is important in the pathophysiology of Sjögren’s disease.”

IL-14 alpha is a Th2 type cytokine that promotes B cell proliferation and maintenance. Based on these and related findings the use of biological therapy has emerged as a focus for treatment. (Biological therapy modulates immune system activity, often using agents that act as biological response modifiers.) Efforts have been made to exploit this understanding as documented in a paper published last year in Autoimmunity Reviews:

“”Conventional therapy (moisturizers, pilocarpine, Cevimeline, local Cyclosporine, and hydroxychloroquine) remains the basis for the treatment of primary Sjögren’s syndrome (pSS) but they do not modify the course of the disease. Rituximab is currently the most fully evaluated biologics in pSS. Open-label studies suggest that Rituximab is well tolerated (although infusion-related reactions and serum sickness remain possible), induces a rapid depletion of B cells in the blood and salivary glands, and could improve early active pSS or pSS with active extra glandular involvement. Two small double blind randomized studies have been conducted and now published, demonstrating its efficacy on fatigue and sicca syndrome in early disease.”

Two larger studies were underway at the time the paper came out, and a paper just published in Expert Opinion on Biological Therapy reviews the evidence available at this time in regard to Sjögren’s syndrome:

“Primary Sjögren’s syndrome (PSS) is a relatively common immune-mediated condition characterized by oral and ocular dryness, fatigue, musculoskeletal pain and poor health-related quality of life. Other extra-glandular organs can also be affected and PSS is associated with a markedly increased risk of lymphoma. Furthermore, the health-economic cost for PSS is substantial. There is currently no effective treatment available. With better understanding of the pathophysiology of PSS and advances in technologies, it is now possible to develop biological therapies to target specific molecules or molecular pathways that are important in PSS pathogenesis. Indeed, a limited number of biological therapies have already been tested in PSS with mixed successes.”

However, biological agents such as rituximab are not easy manage and come with the potential for serious side effects when B-cell activity, necessary for normal immunity, is blocked with a ‘blunt instrument’. findings suggest that we shouldn’t be ‘putting all our eggs in one basket’. An overview of reviews published in the highly respected Cochrane Library highlights the concerns:

“Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates.”

The authors investigated adverse effects from a number of biologics including tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) associated with 163 randomized controlled trials comprising 50,010 participants, and 46 extension studies with 11,954 more participants. Their data sound a cautionary note:

“Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events, number needed to treat to harm (NNTH) and withdrawals due to adverse events and an increased risk of TB reactivation compared to control.”

Clinicians may wish to read the paper in its entirety to see the differences in this regard between the various biologics. The authors conclude:

“Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results…There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics.”

What else can we do to modulate the course of the disease? Identifying and removing agents that trigger and amplify the inflammatory autoimmune activity is an important consideration. Abundant evidence has accumulated linking Sjögren’s syndrome with gluten sensitivity. A study published in The American Journal of Gastroenterology draws attention to this association:

“Many autoimmune diseases occur concomitantly with celiac disease. We investigated prospectively the occurrence of celiac disease and small-bowel mucosal inflammation in patients with primary Sjögren’s syndrome.”

Clinicians know that when autoimmune activity has been set in motion there is rarely only one tissue target for the inflammatory attack. The authors examined 34 patients with primary Sjögren’s syndrome and 28 controls by small bowel biopsy, the presence of intraepithelial lymphocytes (white blood cells within the intestinal lining), DQA and DQB genes for gluten sensitivity, serum antiendomysial and antigliadin antibodies. I find their data to be of special significance:

“Five (14.7%) of 34 Sjögren’s syndrome patients were found to have celiac disease. The density of jejunal intraepithelial γδ+ T cells was increased in all celiac and in four nonceliac patients. All celiac patients, 69% of nonceliac Sjögren’s syndrome patients, and 11% of control subjects showed enhanced HLA-DR expression. HLA DQ2 was present in 19 (56%) patients with Sjögren’s syndrome, including all five with celiac disease.“

A critical point is embedded here: non-celiac autoimmune manifestations of gluten sensitivity have become very common. While a modest percentage of the Sjögren’s syndrome cohort had the celiac disease ‘version’ of gluten sensitivity, most showed activation of the HLA-DR and DQ genes expressing gluten sensitivity. The authors concluded:

“The findings show a close association between Sjögren’s syndrome and celiac disease. Even among nonceliac patients with primary Sjögren’s syndrome, an ongoing inflammation is often present in the small bowel mucosa.”

Research published in the Scandinavian Journal of Gastroenterology adds more evidence to the connection between gluten sensitivity and Sjögren’s syndrome, while cautioning that the gastrointestinal symptoms of celiac disease may not be present. The authors set out to…

“…evaluate the rectal mucosal response to gluten as an indication of gluten sensitivity in patients with primary Sjögren’s syndrome (pSS).”

They exposed the rectal tissue of 20 patients with Sjögren’s syndrome and 18 controls to wheat gluten. Fifteen hours later they measured the mucosal tissue release of nitric oxide (NO). What did they find?

“Five patients with pSS had a significant increase in the luminal release of NO after the rectal gluten challenge, indicating gluten sensitivity. All were HLA-DQ2 and/or -DQ8-positive. Two of the patients with increased NO had antibodies against transglutaminase and a duodenal biopsy showed an absolutely flat mucosa consistent with coeliac disease in one of the patients. Before gluten challenge, 15 of the Sjögren’s syndrome (SS) patients reported gastrointestinal symptoms, and 8 reported intolerance to various food products. No correlation was found between gluten sensitivity and self-reported food intolerance or gastrointestinal symptoms.“

Note again the last point that gluten sensitivity can manifest as an attack on a wide variety of tissue targets without gastrointestinal symptoms. The authors concluded:

“Rectal mucosal inflammatory response after gluten challenge is often seen in patients with pSS, signifying gluten sensitivity. However, this reactivity is not necessarily linked to coeliac disease.“

The authors of a paper recently published in the Romanian Journal of Internal Medicine also comment:

“Celiac disease (CD) is an immune mediated enteropathy with an increasing prevalence worldwide…The clinically silent form affects the majority of patients. Hence, diarrhea, nutritional deficiencies and weight loss are symptoms which are not very often seen.“

They further state:

“The high risk groups have been identified to be those patients suffering from autoimmune insulin-dependent diabetes mellitus, osteoporosis, Sjogren’s syndrome and the first degree relatives of CD patients. Those patients should be screened for CD. The association of CD with several autoimmune ailments has various explanations ranging from common genotypes to systemic immune reactions triggered by food antigens.“

A case report published in the journal Zeitshrift für Rheumatologie is worth noting in this context. The authors state:

“We report on a 26 year old woman with dermatitis herpetiformis Duhring, diagnosed at 10 years of age, who developed arthritis, symptoms of celiac disease, and Sjögren’s syndrome 15 years later. Clinical symptoms, biopsies of duodenal mucosa and salivary glands as well as serological findings established the diagnoses.”

Most importantly…

“Gluten-free diet alleviated severity of clinical symptoms very quickly indicating the basic pathology of celiac enteropathy in the immunological disorders.”

A study published in the journal Clinical & Experimental Allergy alerts us to the fact that other food sensitivities can be involved with Sjögren’s syndrome, in this case cow’s milk protein. The authors note:

“Patients with primary Sjögren’s syndrome (pSS) are reported to have a variety of gastrointestinal symptoms partly attributed to an overrepresentation of celiac disease. We have observed that irritable bowel syndrome (IBS)-like symptoms are frequent complaints in this patient group. Allergic manifestations to various drugs are also common in pSS. A role of food allergy in IBS has been proposed.“

In this case the investigators examined the mucosal response to a rectal challenge with cow’s milk protein (CM) in 21 patients with pSS and 18 healthy controls. Fifteen hours later they measured the mucosal production of nitric oxide (NO) and the release of myeloperoxidase (MPO) as indicators of a mucosal inflammatory reaction. They found that a significant percentage of Sjögren’s syndrome subjects react to cow’s milk protein:

“Eight out of 21 patients with pSS had a definite increase of mucosal NO synthesis and the luminal release of MPO after rectal CM challenge.”

Interestingly…

“This sign of milk sensitivity was not linked to IgG/IgA antibodies to milk proteins.“

Consider the clinical significance that there was an inflammatory response to cow’s milk protein challenge in the absence of IgG and IgA antibodies. Furthermore…

“All patients who were CM sensitive suffered from IBS. In a small open study, patients reactive to CM reported an improvement of intestinal symptoms on a CM-free diet.”

The authors conclude:

“A rectal mucosal inflammatory response after CM challenge is seen in 38% of patients with pSS as a sign of CM sensitivity. IBS-like symptoms were common in pSS, linked to CM sensitivity.”

Taken together, this evidence suggests that it is very important for practitioners and patients both not to overlook the potential role of gluten and other food sensitivities as a causative factor in Sjögren’s syndrome. Clinicians should note that a laboratory panel that does not include the full range of anti-gliadin and transaminase antibodies can be misleading and are urged to employ one that does. The scope of this post does not encompass the use of evidence-based natural agents to modulate immune system function within the functional medicine approach; practitioners are welcome to comment on this post or contact me personally for discussion. But I’ll wrap this up with a study published not long ago in the journal Rheumatology in which the authors set out to…

“…investigate the immunomodulating role of fat-soluble vitamins in 25 patients with primary SS (pSS) and 15 healthy individuals…Nutritional defects, including vitamin deficiencies, are commonly associated with impaired immune responses…”

They measured plasma levels of vitamins A, D and E; natural killer [NK] T cells, T-cell subsets, B cells, IL-10 producing Tr1 cells, CD4+CD25+ Treg cells and Th17 cells, along with a number of Th1- and Th2-soluble and intracytoplasmic cytokines(IFN-γ, IL-4, -10 and -17. They then drew correlations between vitamin levels and immunological and clinical parameters.

“Vitamin A levels did not differ between patients and controls, yet in patients with extraglandular manifestations (EGMs) a significant decrease in vitamin A levels was apparent compared with pSS patients without EGMs. Vitamin E levels were increased in patients compared with controls, whereas vitamin D levels were similar in pSS and control subjects. In patients, vitamin A showed a positive correlation with both NK cell and Th17 cell, and a negative correlation with Schirmer’s test values [Schirmer’s test determines whether the eye produces enough tears to keep it moist.]. Positive correlation was found between vitamin E and NK cells, Th1 cells and the Th1/Th2 ratio. In the control group, we found correlation between vitamin E and serum IL-10 levels [immunoregulating].”

The authors sum up the significance of this in their conclusion:

“Our data suggest that fat-soluble vitamins may be important in immunoregulatory processes in patients with pSS.“

Canker sores and autoimmune thyroiditis

Posted on May 6, 2011 by Dr. Jonathan

It may not be recognized widely enough that recurrent canker sores (aphthous stomatitis) is an autoimmune disorder. A study just published in the Journal of the European Academy of Dermatology and Venereology investigates the association between recurrent canker sores and autoimmune thyroid disease (the most common cause of low thyroid function in developed countries). The authors state:

“Recurrent aphthous stomatitis (RAS) is an autoimmune disorder characterized by the periodic appearance of aphthous lesions on the oral mucosa. TH1 cytokines plays a key role in the aetiopathogenesis. Autoimmune thyroid disease (ATD) is the most common autoimmune disease and is frequently accompanied by various other autoimmune diseases.”

They examined ninety patients and 30 healthy volunteers by measuring thyroid stimulant hormone (TSH), free and total triiodothyronin (fT3, TT3), free and total thyroxin (fT4, TT4), thyroglobulin, and the most common antibodies found in autoimmune thyroiditis, anti-thyroid peroxidase antibody (anti-TPO) and anti-thyroglobulin antibody (anti-TG. They also performed thyroid ultrasonography. Their data showed a connection:

“The anti-thyroid antibody was positive in 31.11% of the patients with RAS, and in only 10% of the individuals in the control group. The mean anti-TG level was also higher in the RAS group. Ultrasonography revealed nodules in 28.8% of the patients with RAS and in 16.7% of the individuals in the control group. The sT4 levels were lower and the TSH, anti-TPO and anti-TG levels were significantly higher in the RAS patients with thyroid nodules than the RAS patients without nodules.”

Rarely is there only one tissue target in an autoimmune state. Personally, I feel that an important question for any practitioner confronting a condition characterized by chronic inflammation is: “to what degree is there an autoimmune component?” The authors conclude:

“The frequency of thyroid autoimmune-related problems was higher in patients with RAS. It would be worthy of searching autoimmune thyroid disorders in patients with RAS.”

The autoimmune aspect of preterm labor

Posted on February 11, 2011 by Dr. Jonathan

A paper just published in PLoS ONE (Public Library of Science) presents findings that expand our understanding of the inflammatory aspect of preterm labor. The authors state:

“Preterm parturition is characterized by innate immune activation and increased proinflammatory cytokine levels. This well established association leads us to hypothesize that preterm delivery is also associated with neonatal T lymphocyte activation and maturation.”

For our lay readership, innate immune activation refers to the cell-mediated ‘first phase’ Th1 immune response versus the ‘second phase’ Th2 antibody aspect mediated by T lymphocyte activation. The authors obtained cord blood samples following normal and preterm deliveries, and deliveries complicated by clinical chorioamnionitis (inflammation of the fetal membranes). What did they find?

“Infants born following preterm delivery demonstrated enhanced CD4+ T lymphocyte activation… Neonates delivered following clinical chorioamnionitis also demonstrated increased T cell activation. Preterm neonates had an increased frequency of CD45RO+ T cells.”

Autoimmune cross-reactions to environmental stimuli fuels a wide range of disorders. Consider the role of gluten sensitivity in a variety of female reproductive disorders. The authors conclude:

“Preterm parturition is associated with neonatal CD4+ T cell activation, and an increased frequency of CD45RO+ T cells. These findings support the concept that activation of the fetal adaptive immune system in utero is closely associated with preterm labor.“

The obvious practical implication is that screening for preterm labor can be accomplished by testing for antibodies to the fetal membranes. In positive cases rational therapy can be applied on a functional basis to address the underlying causes of immune overactivation.

The autoimmune aspect of hair loss

Posted on February 8, 2011 by Dr. Jonathan

A fascinating study was just published in Medicinski arhiv (Medical Archives, Journal of the Academy of Medical Sciences of Bosnia and Herzegovina) that illuminates the type of autoimmune dysfunction involved in alopecia areata, a common cause of hair loss. The authors state:

“Alopecia areata (AA) is a heterogeneous disease characterized by nonscarring hair loss on the scalp or other parts of the body. A wide range of clinical presentations can occur-from a single patch of hair loss (alopecia unilocularis, AUl), multiple patches (alopecia multilocularis, AM) to complete loss of hair on the scalp (alopecia totalis, AT) or the entire body (alopecia universalis, AU). The cause of AA is unknown although most evidence supports the hypothesis that AA is a T-cell mediated autoimmune disease of the hair follicle and that cytokines play an important role.”

The authors set out to evaluate serum concentrations of interferon-gamma (IFN-g, a major proinflammatory cytokine) in 60 patients with AA in comparison to 20 healthy subjects. They also investigated for an association between IFN-g and the clinical type of AA and duration of the disease. What did their data show?

“The serum concentration of IFN-g in patients with AA was significantly higher than that in the control group. Significantly elevated serum IFN-g were noticed in patients with AU type, especially those suffering from AT, compared with both patients with AUI and patients with AM clinical type. There was no significant difference in serum IFN-g concentration between patients with AUI and AM group, as well as between patients with AT and AU. No correlations were found between duration of disease and the serum levels of IFN-g.”

This clearly shows the autoimmune basis of hair loss in general and the role of IFN-g in particular. Autoimmune conditions require a functional approach that uses up-to-date methods to objectively define the underlying causal factors such as IFN-g for treatments that are targeted, physiological and rational. The authors conclude:

“Our findings confirm previously published data that the Th1 type cytokine IFN-g is elevated in the serum of AA patients.“