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Behcet's Disease: Immune Process and the Potential Impact of
Nutritional Supplementation and Pharmaco-Nutrition


Matthew A. Shapiro
Spring, 1994

The following information about the author was supplied by Dot Tutt:
I spoke with Michael Shapiro in 1999. From memory, I believe he stated that he was not a physician or health professional. When he did his Behcet's research, he was attempting to help a friend with Behcet's avoid toxic treatments. By the time he completed his research, circumstances had intervened and he lost touch with his friend. Michael was going to drop the matter but a physician that reviewed the article thought Michael was on the right track and asked him to post it to the internet in hopes of helping others.

Michael came across the phone as very nice and very intelligent but he no longer has a personal reason to continue to pursue his research in this field. He was pleasantly surprised by the positive response he had received from his article and truly hopes his research will benefit someone.

I have not been able to contact him recently - apparently his email address has changed and I cannot locate his telephone number.

Dot Tutt, August 2002


The following is an examination of the modes of action of Behcet's disease as proposed to date by various researchers, and an investigation of the potential of nutritional supplementation and/or dietary modification to reduce the symptoms and possibly stop the progression of Behcet's disease based on postulated effects of such supplementation and dietary modification on various aspects of the immune response to Behcet's.

The drugs currently used against Behcet's disease have mixed effectiveness, and all have dangerous side-effects. If the signs and symptoms of Behcet's disease can be reduced by nutritional supplementation and dietary modification, then a clearly superior option will be available to those suffering from the disease.

The original triggering factor of Behcet's has not been identified yet, but it is suspected that it is a viral infection or streptococcal-related antigens (Powell 1991). Other proposed etiologies include allergic, toxic, and genetic factors.

The progress of the disease may be broken down into three phases: an initial phase, characterized by a Type IV immune response (Cell-Mediated Immunity, delayed-hypersensitivity response), a second phase, characterized by a Type III response (Immune Complex), and a third phase where substantial tissue damage occurs.

Pre-Active and Early-Active Phase: Type IV Reaction

Most references report that in early oral ulcers in Behcet's Disease (BD) (aka Behcet's syndrome, BS), there is an intense lymphomonocytic infiltration (mononuclear T-cells) around blood vessels, but as the ulcer ages, the infiltration of neutrophils (polymorphonuclear leucocytes (PMNL) or polymorphoneuclear neutrophils (PMN)) increases. (Lachmann 1982, citing Grayowski 1966 and Lehner 1969; Fitzpatrick 1987; Lever 1990; Powell 1991).

However, Jorizzo et al (1988) say that it is in late lesions that a lymphocytic (T-cell) perivasculitis is found in mucocutaneous and systemic lesions. Biopsy specimens of early apthae or pustular vasculitic lesions show either fully leukocytoclastic vasculitis or a neutrophilic vascular reaction. This is said to be the earliest mucocutaneous lesion of BD.

Powell (1991) indicates that the two types of cutaneous lesions show different features. Those resembling erythema nodosum (EN) show small vessel vasculitis and perivascular lymphocytic and mononuclear cell infiltration and fibrin deposition in the vessel wall, while the punched out ulcers are characterized by a leucocytoclastic vasculitis (neutrophil infiltrate) with fibrinoid necrosis.

Lachmann (1982) reports that in biopsies of oral lesions from patients with recurrent oral ulcers (ROU) and Bechet's syndrome, a significant deposition of immunoglobulin (Ig) was not detected. However, in older lesions, 2-5 days old, IgG and complement (C3) were found in the basement membrane in almost all of the sixteen biopsies from patients with minor aphthous ulcers. It is suggested that oral mucosa may be the initial source of antigen and that immune circulating complexes (IC) might be reponsible for extra-oral disease, or that immune circulating complexes may be deposited at a later stage in ulceration, possibly after the initial cell-mediated phase has failed.

Lachmann outlines a scheme which attempts to account for most of the immunological findings in ROU and BS, and the shift from an early, predominantly lymphomonocytic infiltration (probably Type IV, cell- mediated immunity (CMI), delayed hypersensitivity) to a later PMNL infiltration with features associated with a Type III (immune complex) reaction.

The scheme proposed by Lachmann is as follows: A microbial/mucosal antigen causes lymphocytes to become sensitized, and there is antibody response to the mucous antigen. This occurs particularly in those with immunogenetic susceptibility. Local epithelial damage occurs and acute phase proteins (found in all cases) are produced. An initial failure of cell-mediated immunity occurs. The antigen is released, and antibodies respond. Circulating immune complexes (antigen-antibody complexes) result. Of these, there are IgA complexes, IgG complexes, and IgM complexes. The IgA may be responsible for blocking chemotaxis and phagocytosis, causing the failure of complexes to clear. These become deposited in tissues, where complement activation increases the chemotaxis of PMNL and the release of enzymes, and where cell-mediated immunity again takes over. The result is multifocal damage.

Lachmann acknowledges that the nature of activation of recurrences is unknown, but says that recurrent infection is an unlikely cause. It is suggested that the IgA system might prove to play a prominent part in BS, as the initial site of the disease is mucous ulceration, and IgA complexes might inhibit PMNL from removing the damaging IgG complexes from the circulation. This will be discussed further in the next section.

Fitzpatrick (1987) reports that monoclonal antibody studies show a defect in T-cell subsets in the preactive phase of Behcet's disease. "This is the phase in which the person complains of mild pain and tenderness in varius joints about 4 to 8 weeks before the development of erythema nodosum or oral-genital ulceration. At this early stage there is a decreased percentage of OKT4 helper cells and a concomitant increase in OKT8 cytotoxic-suppressor cells in peripheral blood. The normal ration of OKT4:T8 cells is over 2:1. In preactive Behcet's disease (but not in active or inactive disease) this ratio is found to be at the abnormally low level of less than unity." Jorizzo et al (1988) agree that this is a consistent finding. Powell (1991) also confirms this, and suggests that it is the cause of the decrease in total peripheral blood T-cells generally. But some wonder if anti-lymphocyte antibodies are responsible for the accelerated loss of T-cell function in this stage of the disease. Fitzpatrick suggests that the physician and the patient pay greater attention to events in the preactive phase.

Kelley (1993) reports that among neurologic manifestations of BS, during active phases, "the cerebrospinal fluid shows elevated total protein, elevated IgA and IgG, mononuclear pleocytosis, and an elevated IgM index, implying intrathecal Ig synthesis." But between episodes, the cerebro-spinal fluid is normal. Generally "levels of serum complement are normal but drop during preactive phases." "Serum complement levels, particularly C9m are high, although they may dip immediately prior to a flare of uveitis."

Finally, Jorizzo et al (1988) report that in general, in vivo cellular immune responses in BD patients are normal against intradermally injected antigens. Reduced natural killer cell activity has also been described.


Evidence indicates that the initial reaction is cell-mediated, delayed hypersensitivity, with mononuclear cell infiltration and, with depressed T-cell response related to a decrease in T-helper cell ratio to suppressor cells, additional evidence being a below-normal or below-active level of serum complement.

Phase II: Type III Reaction

Here we see an increase in immune complex circulation and deposition. "IC might be the principal agents in the change from focal oral ulceration to the involvement of many tissues in BS."

Antigen-stimulated macrophages synthesize Interleuken-1 (IL-1) and attempt to process the antigen, then presenting it to T- helper cells. These in turn activate other cells to produce IL-2 and othe lymphokines. These in turn activate B-cells to produce antibodies. The initial CMI reaction, having failed, still includes the production of IL-1 and 2 and leads to the release of antigen to antibodies. The antibodies (or immunoglobulins, Ig) are produced by B-cells.

The antibodies bind with antigen to form an immune complex (IC) and those phagocytes with receptors for the Fc portion of antibody surround the complex. The antibody also marks the antigen with complement, a series of blood proteins. Complement coats antigens recognized by antibody so that they can be more readily destroyed by phagocytic cells possessing receptors for complement.

Complement activation generates a series of peptides (chemotactic attractors) to attract inflammatory cells (PMN neutrophils) which then ingest antibody-antigen complexes and release hydrolytic enzymes.

Failure of Phagocytosis / Failure of Chemotaxis / Deposition of IC's

1. Evidence of Immune Complexes in Behcet's:

Ball (1986) reports that circulating immune complexes are found in 30 to 50 percent of patients, while others report finding IC in greater than 50% of patients.

"Measurement of IgA, IgG and IgM by radial immunodiffusion was carried out in serum, saliva, and tears (Scully et al 1979). Serum IgA concentrations were significantly increased in the arthritic, neurological and ocular types of BS. Parotid [salivary] IgA concentrations were decreased in the arthritic, ocular and the mucocutaneous types of BS. In contrast, IgA, IgG and IgM concentrations were increased in the lacrimal fluid in most patients...Circulating immune complexes have been detected in BS and ROU by six independent methods...Although there is no clear evidence for a pathogenetic role for IC, the clinical features are certainly consistent with IC disease and a significant association has been recorded between the levels of IC and the clinical indices of disease." (Lachmann 1982).

"Polyclonal increases in serum IgA associated with certain clinical subtypes such as ocular, arthritic and neurologic, have been reported but results from studies of immune complexes, both circulating and in tissues, have not demonstrated consistent changes." (Powell 1991).

Also, enhanced neutrophil migration has been demonstrated in vivo.

Evidence of Complement in Behcet's:

"Serum C3, C4, and CH50 are generally normal in BS (Lehner et al 1979b). However, C3, C4, and C2 were markedly reduced before an attack of uveitis, suggesting complement consumption by the classical pathway (Shimada et al 1974). The involvement of complement in the pathogenesis of BS is supported by electron-microscopical evidence of membrane fragments showing the appearance of complement-induced lesions in the sera of certain patients (Lehner et al 1978a)." (Lachmann 1982).

But in Lehner 1979b, immunofluorescent studies of biopsies from patients with ROU and BS show C3 in the absence of C1q and IgG in most biopsies suggesting that the alternative complement pathway might be activated. (Lachmann 1982)

2. Failure of Clearance of Immune Complexes

Two of the things which can prevent or delay phagocytosis at this stage are antigen size and antigen number.

"If the invader is large, so that phagocytosis is not possible, antibody attached to the invader will activate complement and cause the release of small complement fragments, which attracts neutrophils that release destructive enzymes to remove the invader, be it a multicellular parasite or a sliver of wood." (EHB 1991)

"Clearance of circulating immune complexes occurs when more than one Ig antibody molecule reacts with a soluble antigen so that at least two antibody molecules are located close enough together to form a structure that is recognized by phagocytic cells, or activates complement. Thus early after an antibody response to foreign serum, antigen-antibody complexes will be found wherein antigen is in excess over antibody so that the complexes will essentially consist of one or two antigen molecules and one antibody. These complexes will not be cleared by phagocytosis and deposit in tissues."

One study showed that 42% of patients with BS and 17% with ROU had a depressed phagocytic activity. A defect was found in 73% of patients with the arthritic and in 58% with the ocular type, but no patients with the muco-cutaneous type had a depression in phagocytosis. (Lachmann 1982)

As mentioned earlier, Powell (1991) confirms that there is a decrease in total peripheral blood T cells (in the pre-active phase), resulting primarily from a reduction in the T-helper/inducer population. Does this continue to have an effect in the active phase? There was also an overall increase in the proportion of activated T cells with all subsets of T cells contributing to this, indicating marked cellular activation.

Powell's comments on NK cell activity may also help to explain the failure of phagocytosis: "In patients with active disease an increase in NK cells in peripheral blood is reported; however, their killing activity against K562 target cells is reduced and this may be related to immature forms of NK cells being released into the circulation."

The Effect of IgA on Clearance of IgG

"IgA complexes suppress chemotaxis of PMN leucocytes [a depressed response to chemotactic stimuli shown in patients with BS and to a lesser extent ROU (Abdulla & Lehner 1979)] whereas IgG complexes may stimulate the release of serum chemotactic factors [explaining increased chemotactic activity in the serum from patients with BS (Matsumura & Mizushima 1975; Sobel et al 1977)]. It is conceivable that the IgA complexes lead to a failure of clearance of the potentially more tissue-damaging IgG complexes." (Lachmann 1982)

These authors infer that because the initial site of the disease is oral ulceration, and since IgA complexes suppress chemotaxis of PMN leucocytes (because they don't fix complement and because they are dominant in the mucosal system), IgA complex may inhibit the clearance of IgG complex from circulation. Does what is causing the oral ulceration cause an increase in IgA, blocking chemotaxis later?

A Brief Look at IgA

First of all, unlike IgG and IgM, IgA's antibody activity is in "external secretions": IgA has a central role in the mucosal immune response.It operates more efficiently than other Ig's in the mucosal environment due to a number of structural features. It does not react with components of either the classic or alternative complement pathway, except possibly when

highly polymerized or in the form of an immune complex; even in the latter instance, it does not bind C3b and therefore does not recruit inflammatory cells and mediators. Also, while it facilitates phagocytosis in the presence of specific antigen, it actually down-regulates phagocytosis in the absence of the antigen. These facts suggest that free IgA (i.e., IgA not associated with antigen) has anti-inflammatory effects, useful in an area of the body replete with materials that can induce excessive inflammatory responses. IgA does have certain pro-inflammatory functions as well, enhancing the production of lactoperoxidase and lactoferrin, and possibly to mediate antibody-dependent cellular cytotoxicity reactions.

IgA binds to SC (secretory component, a protein) for transport. This transport occurs in the digestive tract, the salivary glands, the bronchial mucosa, and the lactating mammary glands. It also occurs in the uterine epithelium and in the liver. Hepatic uptake of IgA may be one mechanism whereby IgA secreted into the circulation is re-directed back into the mucosa, possibly to clear antigenic material that has penetrated the mucosal barrier and become bound to circulating IgA; this has not yet been established in humans.

One in seven-hundred Americans has an IgA deficiency. Subjects with low IgA levels and normal IgM and IgG levels show increased absorbtion of macromolecules and high levels of circulating immune complexes following ingestion of antigens. This may be the cause of the increase in autoimmunity associated with the deficiency.

IgA does occur in the circulation. Mucosal and circulating IgA in have different origins. Bone marrow is the source of most circulating IgA (monomeric IgA1). This type of IgA may be better suited than other forms of IgA to mediate the clearance of mucosal antigens from the circulation because a monomeric IgA1 molecule may form smaller, more non-pathogenic complexes with circulating antigens than polymeric IgA, yet retain the capacity to undergo removal via interaction with appropriate receptors in the liver.

In sum, IgA has a highly focused response to stimuli, which produces antibodies that interact with and eliminate potential pathogens, without at the same time evoking undue inflammation. On the other hand, it also elaborates suppressor elements that interact with ubiquitous antigens and thus down regulate responses both in the mucosal areas and in systemic lymphoid tissues. It is a "gatekeeper" of the immune system via its role in the mucosal immune system. In Behcet's, could it be the case that circulating IgA "chasing" antigens originating in the mucosa reduce chemotaxis and phagocytosis for the IgG complexes, leading to their deposit in tissues?

"The size of an immune complex is very important in regulating its clearance- in general, larger complexes are rapidly removed by the liver within a few minutes, while smaller complexes circulate for longer periods...Anything which affects the size of complexes is therefore likely to influence clearance." IgA complexes are small; but then these are not the complexes found deposited in Behcet's patients. "IgA complexes bind poorly to erythrocytes but disapper rapidly from circulation, with increased deposition in the kidney, lung and brain." But still, IgA complex doesn't trigger inflammation.

When large amounts of complex are present, the mononuclear phagocyte system may become overloaded.

Deposition of Complexes in Tissues of BD Patients

Immunofluorescence staining shows IgM, IgM and C3 deposits within vessel walls."(Ball 1986)

"Immunofluorescent studies show deposition in the vessel wall of IgM, IgG, and IgA associated with C3 and C9, suggesting an immune complex mechanism." (Gambit et al, 1979)

"The most important trigger for tissue deposition of immune complexes is probably an increase in vascular permeability." (Roitt 1985)

Vascular Permeability: CIC's may be caused to deposit by the infusion of agents which cause liberation of mast cell vasoactive amines, including histamine. Complement, mast cells, basophils and platelets must all be considered as potential contributors to the release of vasoactive amines.

The process of inflammation causes increased vascular permeability. At the site of tissue damage, platelet adhesion and Hageman factor are activated. These initiate the clotting pathway. "Further platelet aggregation and release reaction are enhanced by thrombin generated during the clotting pathway and by thromboxane A2 and adenosine diphosphate released from activated platelets. In addition, activated platelets release serotonin and a range of cycloxygenase and lipoxygenase products, which exhibit vasodilatory and chemotactic properties. This reaction is further amplified by the inflammatory process as stimulated mast cells relase PAF (Platelet Activation Factor) and inflammatory cells release thromboxane A2, both of which are potent platelet activators and cause increased vascular permeability." This leads again to the activation of the complement cascade.

C3a and C5a are most significant in inflammation, inducing the release of PAF and histamine from mast cells causing increased vascular permeability and fluid exudation. C5a is also chemotactic for neutrophils and macrophages, recruiting them into the injured tissue. It also causes the release of lysosomal enzymes, leukotrienes, and oxygen radicals. "Thus, increased vascular permeability mediated by PAF, histamine, thromboxane A2, C3a, and C5a facilitate the extravasation of inflammatory cells in response to chemotactic stimuli relased in the area of tissue injury."

Haemodynamic Process: Higher blood pressure and turbulence = more likely immune-complex deposition. This accounts for deposit in the glomerular capillaries. At other sites, like the walls of arteries, the most severe lesions occur at sites of turbulence, such as vessel bifurcations, or in vascular filters such as the choroid plexus or the ciliary body of the eye. (Sell, 1987).

Tissue Binding of Antigen: Local blood pressure doesn't account for why complexes home in on different organs in different diseases. It is possible tha in different diseases antigens will be identified with affinity for particular organs.

Size of Complexes: Discussed above.

Three other factors are size of complex and Ig class (discussed earlier) and complement solubilization, which we won't go into.

Jorizzo et al (1988) place their emphasis on the following hypothesis:

"We believe that mucocutaneous and possibly systemic lesions in Behcet's disease results from immune complex-mediated damage such as occurs in necrotizing venulitis. We suspect that an unidentified heat-stable serum factor enhances neutrophil migration and helps to explain the pustular, rather than simple palpable purpric, nature of the lesions in BD. Obviously the neutrophil studies require confirmation and expansion. In addition, studies directed at discovering a specific antigen or group of antigens in circulating and in vessel-based immune complexes are required."


"Autoantibodies to saline homogenates or oral mucosa were found in patients with ROU and BS. Significant haemagglutinating antibodies were detected in 72-80% of MiAu, MjAu and BS but not in a variety of controls (Lehner 1964a). These antibodies belong predominantly to the IgM and to a less extent, IgG classes. In another study haemagglutining antibodies to oral mucosa were, however, found most in BS (Oshima et al 1963). These antibodies were not specific to oral mucosa, as common antigenicdeterminants were shared between the saline extract of oral mucosa, pharynx, larynx, oesophagus, conjunctiva, vagina, skin and colon (Lehner 1969b)." (Lachmann 1982)

"Circulating autoantibodies are present, but only weakly positive in about one-third of patients." (Fitzpatrick 1987)

"Circulating autoantibodies to oral mucosa cells are found in 42 percent of persons during acute flares of Behcet's disease compared with 16 percent of controls [and none in persons with ROU but no other BS symptoms]. Anti-myelin antibodies appear in more than 70 percent of persons with neurologic complications of Behcet's disease." (Ball 1986).

Autoimmunity is defined as the formation of immune products such as antibody or B and T cell receptors, that recognize autoantigens.

When the immune response is directed not against foreign antigens but against self-antigens. Normally during development, a person develops a condition that prevents him or her from recognizing his or her own tissue as foreign (called "tolerance"). Tolerance may be lost and autoimmunity may occur. There are a number of mechanisms which can cause this. One mechanism suggested for Behcet's is that there may be cross-reactivity with a microbial antigen similar to that of oral mucosa.

Disease manifestation is based on the location of the self-antigen and on which of six immunopathologic mechanisms are activated.

"Defective phagocytic capacity, due to abnormal Fc receptor function on macrophages, occurs in autoimmunity, as either a cause or an effect of circulating antibody-antigen complexes. This defect may prevent the normal clearance of autoreactive T cells that escape censoring mechanisms in the thymus."(EHB)


The unknown antigen, probably triggering an autoimmune response, appears to be released from the oral mucosa and become bound with antibody in circulating immune complexes. Whether because of IC size, overloading of the mononuclear phagocyte system (also impaired by decreased NK cell effectiveness), serum IgA reducing chemotaxis, or other reasons, IC's fail to clear and become deposited in tissues. Increased vasopermeability helps to allow the CIC's to become deposited in tissues.

Phase III: PMN Infiltration, Inflammation, and Tissue Destruction

PMN work more in tissues than in blood. Thus the increased activity after deposition of IC's.

PNN Chemotaxis

The important activated complement fragments for inflammation are C3a, C4a, and C5a.

"Activation of these products produces constriction of endothelial cells (anaphylatoxin), permitting blood components to pass into the tissue." C5a is also highly chemotactic for PMN's. PMN's are the hallmark of acute inflammation. Other chemotactic factors for PNM's are N-formyl oligopeptides (derived from bacteria itself), denatured proteins, interleukin-8, phospholipid, and leukotriene B4 (LB-4).

"LTB-4 is believed to play a critical role in the recruitment and activation of inflammatory cells at the site of tissue injury."(EHB 91).

Among the immunological abnormalities associated with Behcet's is increased chemotactic activity of PMN's, with increased lysosomal enzymes in the serum.

PMN Antimicrobial Systems (Oxygen and Enzyme)

"Neutrophils are characterized by numerous cytoplasmic granules that contain highly destructive hydrolytic enzymes...phagocytosis by neutrophils is usually accompanied by the release of the lysosomal enzymes from these cells into the tissue spaces, particularly if the antigen is difficult for the PMN neutrophil to ingest. The lysosomal acid hydrolases cause local tissue digestion at the site of the reactions. The characteristic lesion is fibrinoid necrosis- areas of acellular digested tissue that look like fibrin but lack any fibrillar appearance. Reactive oxygen metabolites, primarily involved in bacterial killing, may also damage infiltrating neutrophils and adjacent tissues, resulting in the formation of pus." Pus---hypopyon? (Sell 1987)

The "respiratory burst" is an interaction of material with cells resulting in a burst of oxidative activity. During the phagocytic process and the delivery of the engulfed material to the lysosomes, a burst of oxidative metabolism ensues, which generates oxygen-free radicals believed to be responsible together with lysosomal enzymes for the intracellular killing of microorganisms. At the same time, this respiratory burst provides oxygen radicals needed for lipid oxidation and the generation of proinflammatory leukotrienes and prostaglandins. In addition, the release of connective tissue- degrading enzymes (collagenase, proteoglycanase), lysosomal enzymes and oxygen metabolites to the extracellular environment causes further damage to the connective tissue and basement membranes underlying the endothelial cells. This process of amplification of the inflammatory response, if persistent, may lead to further tissue damage and a transition from acute to chronic inflammatory reaction.

Reactive Oxygen Species (ROS's):


Superoxide anion

Hydroxyl radical: hydrogen peroxide and superoxide.

Singlet oxygen

Hydrogen peroxide: a substrate of myeloperoxidase.

Hypochlorous acid: produced by the reduction of hydrogen peroxide by myeloperoxidase in the presence of chloride.

Superoxide production also takes place via 5HPETE, an early player in the conversion of arachidonic acid to Leukotriene B4 (LTB-4).

Tissue Destruction from Radicals

Specifically, the superoxide anion, hydrogen peroxide, the hydroxyl radical, and hypochlorous acid (HOCl) have all been associated with tissue destruction and the inflammatory process. These products are considered to be highly cytotoxic.

The Body's Defenses Against Oxidative Damage

Superoxide Dismutase (SOD) is an enzyme which is a highly effective scavenger of superoxide radicals. There are two types of SOD produced in the body: extracellular (EC-SOD), a copper-containing enzyme present in high amounts in lungs, thyroid, and uterus, with small amounts in the blood stream, and copper-zinc SOD, present within most cells, primarily within the cytosol. It protects intracellular components from oxidative damage, converting the superoxide anion (O2-) to hydrogen peroxide.

Catalase is a heme protein that catalyzes the reaction converting H2O2 to oxygen and water catalase. It is usually found in peroxisomes. Catalase provides a protective role similar to that of glutathione peroxidase in most cells. Together with SOD, catalase provides a rapid means of equilibriating and detoxifying superoxide anion and hydrogen peroxide in cells. In addition, both enzymes have considerable use as pharmacologic agents to decrease the effect of oxygen radicals in human disease.

Glutathione peroxidase (GSH-Px) prevents cell damage from oxidative stressors such as H2O2 and organic hydroperoxidase. One of the integral components of GSH-Px is selenium, and it has been reported that restricted dietary selenium leads to a reduced GSH-Px activity in serum and red cells, and diminished antioxidative capacity of the body. Delilbasi et al (1991) found a decreased level of selenium in patients with Behcet's disease. A further discussion of this finding is included below.

There are also a number of non-enzymatic defenses, notably glutathione, ascorbate, and a-tocopherol. These will be discussed in more depth below.

Superoxide Production and Scavenging in Behcet's Patients

Warren et al (1990) examined the role of oxygen metabolites in the tissue damage associated with neutrophil influx into sites of immune complex deposition, focusing on acute dermal vasculitis and alveolitis in rats. They report that in the lung, catalase and deferoxamine are highly protective, but that SOD has a transient protective effect. The xanthine oxidase inhibitors, allopurinol, and lodoxamide, are also protective. In the skin, neither catalase nor deferoxamine is protective, "suggesting that H2O2 and iron are not absolutely required for the development of dermal vasculitis." In the skin, both SOD and inhibitors of xanthine oxidase have protective effects. In both the lung and skin, the protective effects of SOD and xanthine oxidase inhibitors are paralleled by reductions in neutrophil influx into sites of injury. In contrast, catalase and deferoxamine have no effect on neutrophil accumulation. The authors felt that the study provided evidence that O2- contributes significantly to the accumulation of neutrophils.

Pronai et al (1991) report that enhanced O2- generation by PMN's can mediate tissue damage associated with Behcet's disease. These researchers examined whether the superoxide scavenging activity of PMN, mononuclear cells, or plasma has a correlation to the amount of O2- generated by PMN in Behcet's. It was found that in Behcet's, O2- release by both non-stimulated PMN and those stimulated with opsonized zymosan or PMA was enhanced. The superoxide scavenging activity of PMN, but not mononuclear cells and plasma, was significantly lower in BD patients as compared with healthy controls. The superoxide scavenging activity of PMN showed a strong negative correlation with their O2- release. The superoxide scavenging activity (SSA) of PMN was lower in BD patients with elevated erythrocyte sedimentation rates and C-reactive protein levels than in subjects with normal test results.

These researchers also found that colchicine treatment increased the SSA of PMN toward normal levels in BD patients. (Remember, colchicine works by reducing the chemotaxis of PMN's). However, while colchicine could prevent the decrease in the SSA when PMN were stimulated with opsonized zymosan, it could not when stimulated with PMA. Their results suggested that the enhanced O2- release by PMN in vivo may be responsible for the decreased SSA of PMN in Behcet's and the PMN [surviving autooxidative attack?] might be able to release more O2- in tissues.

Pronai et al (1990) report that protection from O2- is provided by SOD inside of cells, and that it has been shown to be effective in the treatment of both RA and BD, but lament the lack of data about SOD-like activity of PMN in BD. A study was conducted using both RA and BD patients. Results showed that the SSA of PMN was about half in both RA and BD as compared to that in healthy controls. There was no difference in the SSA of mononuclear cells, however. SSA of PMN in BD was lower in the group with complete BD symptoms than in the incomplete group, but not to a statistically significant degree. There was no difference between active and inactive BD. Lower SSA was significantly lower in patients with elevated erythrocyte sedimentation results. Absolute numbers of PMN were not correlated with the SSA of PMN. SSA of patients receiving colchicine was siginificantly higher than in those without the drug. NSAID did not make a difference. The researchers offered two possibilities to explain why the increase in PMN activity in both RA and BD is correlated with an increased superoxide radical production. First, the activity of SOD is lower, favoring the increase of intracellular O2- production. The deficient SSA observed may be attributed to problems either in gene expressions of SOD or dysfunctions in the induction mechanisms in both diseases. But evidence is against this hypothesis, as no such change has been found in RA (not examined in BD), and the fact that the productions of the two types of SOD (Mn-SOD and Cu/Zn-SOD) are independent, genes located on different chromosomes, and the fact that the activity remained unaltered in mononuclear cells. Dysfunction in the induction mechanism is possible, but all other PMN functions were enhanced rather than deficient in both RA and BD.

The second possibility offered is that the oxidative species such as superoxide radicals, hydroxyl radicals, or hydrogen peroxide, may inactivate SOD. If so, the primary cause of decreased SOD activity would be the increase of O2- generation itself. The researchers hypothesized that the induction of SOD by O2- radicals may not be sufficient compared to the amount of O2- generated by PMN in either RA or BD. Conversely, O2-,H2O2 or both may inactivate SOD inside the cells. Accepting the "inactivation theory of SOD", it is suggested that active PMN (with possibly higher O2- generation rate) have lower SSA.

Colchicine had a protective effect against the decrease in SSA of PMN in this study. Since the researchers used OZ to stimulate the PMN, and OZ stimulates the O2- generation by stimulating phagocytosis itself, and since colchicine blocks phagocytosis, it is hypothesized that colchicine prevented the decrease in SSA of PMN by blocking the O2- generation of the cells indirectly. That is, SOD was not enhanced directly, but through a reduction in the production of radicals which may inactivate SOD, this reduction in radicals effected by blocking phagocytosis.

Pronai and Arimori (1992) investigated further the SSA of plasma in patients with rheumatoid arthritis, systemic lupus erythematosus, polymyo-dermatomyositis, progressive systemic sclerosis, myaesthenia gravis, and autoimmune thyroid disease. Plasma superoxide scavenging activity was significantly lower in RA, SLE, PM, and PSS, but not in MG and AT, as compared with healthy controls. An inverse correlation was observed between plasma SSA and erythrocyte sedimentation rates, absolute number of leukocytes, C-reactive proteins, and serum globulin levels. Patients treated with prednilosone (a corticosteroid), especially ones with RA, showed an increase in plasma SSA. They also found that Ge-132 (carboxyethylgermanium sesquioxide) promotes prednilosone effects. "Our results indicate that a decrease in plasma SSA is not disease specific, but inversely correlates with the severity and activity of inflammation."

In one study (Niwa et al 1985), patients showing an increase in neutrophil active oxygen generation, including those with Behcet's, rheumatoid arthritis, Crohn's disease, and progressive systematic sclerosis, were treated with injections of liposomal superoxide dismutase (SOD), 2.5 mg twice a week. There was a marked reduction in 12 out of 16 patients with active Behcet's disease, with particular effectiveness against intestinal manifestations. Remission rates in other diseases were 7 out of 8 mucocutaneous lymphnode syndrome / Kawasaki disease, 3 of 5 dermatitis herpetiformis, IgA linear bullous dermatosis or severe cement dermatosis, 4 out of 9 severe and active rheumatoid arthritis, 3 out of 3 PSS, 4 out of 4 Crohn's disease, 3 out of 4 colitis ulcerosa, and 2 out of 2 unresponsive (hemolytic) anemia. Several terminal-stage PSS patients showed dramatic improvement. The researchers reported no toxicity from liposomal SOD, which had various advantages compared to free SOD preparations.

It appears that just when the body needs more superoxide scavenging activity to protect its tissues, whelevel of SSA falls. Pronai et al suggested that the increased superoxide production may deactivate SOD, reducing SSA. Or the PMN's themselves may be damaged, causing the decrease in SOD production and level of scavenging activity. Madazero et al (1990)

report that autooxidation plays a key role in PMN dysfunction. Apparently, PMN become more vulnerable to their own oxygen metabolites during periods of extreme stress such as re-injury of tissues, major surgery, or systemic infections. Two of the factors protecting PMN's are a-tocopherol and ascorbic acid (Vitamins E and C)..."Low cellular a-tocopherol content in trauma patients suggests that total tissue a-tocopherol availability is compromised at the time when it is most necessary, as indicated by diminished PMN-reducing capacity and increased consumption of a-tocopherol in thawed sera...Since PMN functions such as locomotion, phagocytosis, and microbial killing are membrane-dependent activities, deficient serum and cellular ascorbic acid and a-tocopherol will render PMN more sensitive to oxygen metabolites, resulting in PMN dysfunction in hyperactivated states."

Madazero et al continue: "We observed excess oxidative capacity or diminished reducing capacity in the sera and PMN of trauma patients [as observed with O2- and SOD in Behcet's patients- my note]...the deficiency of ascorbic acid and a-tocopherol in trauma is expected to result in greater risk to autooxidative injury and may in fact contribute to injury, if it is not the major cause of the PMN dysfunction in trauma...In view of these, we should now consider studying whether replacement therapy with ascorbic acid and a-tocopherol at amounts enough to replenish serum and cell concentrations to normal will reverse or hasten the resolution of PMN dysfunction..."

Wolf (1993) describes the process of ascorbic acid uptake by human neutrophils and cites Washko et al's (1993) in vitro study of this process. The activation of neutrophils provides the oxidizing capacity to convert extracellular ascorbic acid to dehydroascorbic acid, which is rapidly absorbed through the cell membrane. However, with activated cells in the presence of oxygen radical scavengers superoxide dismutase and catalase, the rise in intracellular ascorbic acid was abolished. This indicates that the PMN depends on extracellular oxidants to raise its intracellular level of protective ascorbic acid.

Washko et al (1993) refer to the level of ascorbic acid used in their incubations (200 micromol/L) as "the higher end of the physiologic range" for human serum. While ascorbic acid levels rise with increased dietary intake, it seems that a saturation level is reached at 80-90 micromol/L, which is equivalent to a dietary intake of 70-140 mg/day. Above this level, renal clearance of ascorbic acid rises sharply, which explains why an intake of 1500 mg per day is only 50% absorbed, while an intake of 400 mg is almost completely absorbed. But Wolf wonders openly whether Washko et al would have obtained similarly high rates of antioxidant recycling at concentrations of ascorbic acid less than the 200 micromol/L used and closer to the physiologic range.

Mizushima et al (1991) prepared an SOD cream from bovine SOD and applied it to the skin and mucosal lesions of patients with, among other diseases, BD. It was demonstrated to be more effective than steroid ointment. The four patients with Behcet's showed substantial improvement. The study was not a controlled trial, however, and the therapeutic activity of the SOD cream might be partly due to sodium hyaluronate (added to maintain hydration and permit easier spreading of the cream). Sodium hyaluronate acts on tissue repair and has a weak active-oxygen scavenging effect. The authors offer the possibility that the ratio of lipid peroxide radicals to SOD in skin lesions, important for the healing of lesions following burns and irradiation, is the factor explaining the action of the SOD cream.

Selenium, The Immune System, and Behcet's

Delilbasi et al (1991) found that serum selenium (Se) in Behcet's patients were 60% of those in healthy subjects. They also found that IgG and IgM levels for the BD group were substantially lower than in healthy subjects. The authors pointed out that many diseases are associated with low serum Se levels, and explain that a deficiency of Se has been associated with inhibited resistance of microbial and viral infections, neutrophil function, antibody production, proliferation of T and B cells in response to mitogens, and cytodestruction of T lymphocytes. The researchers postulate that the presence of hydroperoxides and their products connected to Se deficiency in the serum or plasma of patients may play an important role in the etiology or prognosis of Behcet's Disease. They did not indicate what the cause of the selenium deficiency might be.

They also did not offer an explanation for the discrepancy between their findings of lower IgG and IgM levels, against others' (Lehner, O'Duffy) findings in 1971 of increased levels of IgA, IgG, and IgM in the acute stage of Behcet's disease.

Glutathione, an antioxidant in its own right and part of one of the chain-breaking, scavenger antioxidants, is produced by the body, and Madazero et al did not find a reduced level in the sera of trauma patients as they did with externally-supplied ascorbate and a-tocopherol. However, glutathione peroxidase requires selenium, which is not produced by the body. The serum selenium deficiency found in Behcet's patients could inhibit hydrogen peroxide and hydroperoxidase scavenging activity, allowing greater tissue damage. Delilbasi et al allude to this with in reference to a possible connection between selenium deficiency, lower platelet GSH-Px activity, and acute myocardial infarction. Depressed selenium levels causing decreased GSH-Px activity could result in increased platelet aggregation and an increased risk of thrombosis, a dangerous feature of Behcet's Disease.

Nutrition Reviews (8/88) reported that low serum Se concentrations observed in rheumatoid arthritis patients are not necessarily associated with low activities of SeGSH-Px (glutathione peroxidase), since only about 15% of plasma Se is associated with the enzyme. The correlation between low serum Se levels and the activities of SeGSH-Px seems to vary according to tissues and possibly other factors.

The journal reported a study by Tarp et al (1987) in which RA patients were given 250 micrograms per day in the form of a tablet of Se-enriched yeast daily for 26 weeks. Before therapy, RA cases had poorer Se status than controls by all parameters except platelet GSH-Px. As a result of supplementation, both RA cases and controls showed increased blood Se levels. Controls failed to show increases in serum and erythrocyte SeGSH-Px levels, indicating that each may already have been at a maximal level. The RA cases showed increases to the level of controls, exceeding them in fact in erythrocyte Se, in each parameter of Se status except granulocyte SeGSH-Px status. The fact that granulocyte SeGSH-Px status responded poorly to oral Se was significant "in view of the known need of such phagocytizing cells for antioxidant protection against reactive oxygen species [ROS]." Tarp et al suggested that the phenomenon of limited GSH-Px production in these cells might result in a situation wherein inflammation is maintained due to the accumulation of ROS within the cell, ultimately leading to premature cell death.

Selenium seems to have had mixed results against RA, and any role of SeGSH-Px seems to be indirect. (NR 8/99)


I. The drugs used in treating Behcet's patients, their modes of action, and side-effects.


Used in pharmacologic doses to stabilize leucocyte lysosomal membranes, prevent the release of destructive acid hydrolases from leukocytes, inhibit macrophage accumulation in inflammed areas, reduce leukocyte adhesion to capillary endothelium, decrease complement components, decrease Ig and complement concentrations, and to decrease passage of immune complexes through basement membranes. May depress reactivity of tissue to antigen-antibody interactions.

Systemic corticosteroid therapy is indicated for clinically significant Behcet's disease, which affects more than just mucocutaenous sites. It is effective against the latter, but is avoided because of side-effects of long-term therapy. The therapy may be unsuccessful in controlling severe ocular and neurologic lesions and probably does not affect the nonvasculitic vessel disease (Jorizzo et al 1988).

While cortico-steroids work well against primary IgA production, they don't work against the secondary production, which is much greater.

"Today, steroids are the most effective drugs in clinical use [discussion not in context of Behcet's specifically] and are capable of inhibiting neutrophil and monocyte infiltration to inflamed sites as well as the production of the cytokines TNF and IL-1. However, the toxic side effects of steroids are prohibitive of widespread clinical use." [To be continued in Lipid section].(EHB 1991)

Corticosteroids are antagonists to vitamin A, the B-complex vitamins, calcium, magnesium, phosphorus, vitamin K, vitamin D, and zinc. May decrease serum concentrations of vitamins C and A.

Colchicine: Used against ocular inflammation and skin disease. A cortico-steroid. Reduces recurrences of ulceration, possibly because it is a strong inhibitor of PMN chemotaxis.

Gurer et al (1991) concluded that colchicine inhibits inflammation and PMN chemotaxis by inhibiting the cycloxygenase and lipoxygenase pathways of arachidonic acid metabolism.

Colchicine causes malabsorbtion of all nutrients, including sugars, fats (and the fat-soluble vitamins A, D, E and K), protein, iron, vitamin B-12 and folic acid. The side effect of diarrhea causes loss of minerals.

Indomethacin is an NSAID (Non-Steroidal Anti-Inflammatory Drug) which, according to the drug references, is as effective in short-term use as colchicine and is better tolerated. Indomethacin is indicated for polyarthritis. The NSAID's, which include aspirin, inhibit the cycloxegenase pathway.

Prednilosone: A steroid. Used against ocular inflammation, and with azathioprine and chlorambucil against oral and genital ulcers. Lowers serum C3 levels toward normal. Found to increase superoxide scavenging activity in patients with rheumatoid arthritis. "Reduces symptoms; does not affect progression of disease [in rheumatic and collagen diseases]." It increases susceptibility to infection, among numerous possible side effects.


Azathioprine (Imuran): In Behcet's it is used for oral ulcers, particularly in assistance to prednilosone. Yazici et al (1990) found that azathioprine, when used in combination with cortico-steroids, prevented new eye disease among Behcet's patients. They also reported less frequent oral ulcers, genital ulcers, and arthritis. According to the PDR, azathioprine suppresses disease manifestations as well as underlying pathology in animal models of auto-immune disease. How it does this is not known. It is an immunosuppressive, CMI response being suppressed to a greater degree than antibody responses.

Along with the usual dangers associated with immunosuppressives, the use of azathioprine carries a risk of neoplasia. It has been found to be mutagenic in animals and humans, and carcinogenic in animals. Severe leukopenia and/or thrombocytopenia may occur.

Cyclosporine: An immunosuppressant. Inhibits CMI response. Inhibits immunocompetent T-cells. Neutralizes IL-2 secreted by OKT4 suppressor cells. Some have found that it inhibits B-cell responses to macrophage-processed antigens and directly suppresses B- cell production, while others have found no effect on B-cell production and no effect on phagocytic cells in animals. Widely used to prevent transplant rejection. Is reported to have been been used effectively to treat patients resistant to prednisone, azathioprine, and chlorambucil. "Renal and other toxicity, however, may limit its usefulness."

Chlorambucil: An immunosuppressive alkylating agent used in severe cases. "Risks of chrosomal damage andinfertility...suggest that oral prednisone and azathioprine should be used first." (Jorizzo et al 1988). Interferes with DNA replication and transcription of RNA; disrupts nucleic acid function. Carcinogenic potential. Used to assist prednilosone against genital ulcers.

Other Drugs:

Levamisol (Ergamisol): Used with fluoroacil against colon cancer. In Behcet's it is used for oral-genital ulceration. An immunomodulator; it appears to restore depressed immune function (rather than stimulate it to above normal levels). Can stimulate the formation of antibodies to various antigens, enhance T-cell responses, and increase neutrophil mobility, chemotaxis and adherence. It is recommended for use only after colon cancer surgery with fluoroacil. Levamisol can cause many adverse reactions.

Dapsone: An anti-infective. May act as an immunomodulator when used to treat certain dermatologic diseases. Used against mucocutaneous lesions in lupus when resistant to corticosteroids. It is also used in some AIDS patients. Does not affect cutaneous IgA and complement deposition. It may inhibit the alternate pathway of complement and interfere with the myeloperoxidase-H202-halide cytotoxic system within neutrophils. It also appears to inhibit spontaneous and induced synthesis of PGE-2 by PMNL obtained from healthy individuals or patients with leprosy.

Dapsone is carcinogenic in animals.

Thalidomide: Has been found to be effective against mucocutaneous ulcers and arthritic symptoms. Trial results showed that it reduces circulating immune complexes and CIC-mediated vasculitis but has no effect on PMN migration or chemotaxis. Due to its teratogenic effects, it was removed from the market thirty years ago. Can also cause neurologic problems.

Prostacyclin (PGI-2): Injected to halt incipient thrombo-phlebitis. Prevents platelet aggregation.

II. The Alternative

Clearly, the drugs used against Behcet's disease have a shotgun effect- they do not allow for selective attacks in areas where Behcet's disease appears to be doing its harm. They may also cause worse diseases (cancer), and can harm the body's natural defenses through depletion of nutrients. The following is a discussion of an alternative approach: the use of nutritional supplementation and modification.

1. n-3 Fatty Acids

In a letter to the British Journal of Medicine in 1989, Kurkcuoglu et al described the results of an experimental treatment of three Behcet's patients, all with painful oral and genital aphthae and having positive pathergy tests. Having heard that dietary supplementation with eicosapentanoic acid (EPA) had been found to be beneficial in the treatment of patients with rheumatoid arthritis, atopic dermatitis, and psoriasis, they decided to see if it would help their patients. All three patients had been treated previously with oral colchicine, prednilosone and dapsone without any satisfactory improvement. While on the trial they did not take any other drugs and received ten capsules of MaxEPA (a trade name for a concentrated form of fish oil rich in EPA), for a total of 1.8 g EPA daily.

During the first four weeks of therapy, the patients had only one episode in which they developed oral and genital aphthae, and the pathergy test became only weakly positive. After 8 weeks on the trial, two of the patients were completely free of lesions but one had a further episode of oral aphthae that resolved in a few days. After 12 weeks, none of the patients had any lesions.

The Arachidonic Acid Cascade

Some of the most important chemicals in the inflammation process are the prostaglandins (PG) and the leukotrienes (LT). These are known as eicosanoids, the end products of what is called the arachidonic acid cascade. An important determinant of what kinds of eicosanoids are produced is the level of arachidonic acid (AA) present in and released from cell membranes. The dietary intake of linoleic acid (n-6, "omega-6") affects the availability of the arachidonic acid "pool". Another important factor is the level of eicosapentanoic acid (EPA) in the cell membranes, and this is determined by the dietary intake of alpha- linolenic acid (n-3, "omega-3"). (Note that linoleic and linolenic are different words).

There are two pathways by which the metabolism of AA and EPA are further metabolized. They are the cycloxygenase pathway and the 5-lipoxygenase pathway. The cycloxygenase pathway leads to the production of PG's and thromboxane (Tx), and the 5-lipoxygenase pathway leads to the production of LT's. All are vital to the body's normal healthy function. However, an excess of n-6 over n-3 in the diet and in the cells means that a more potent variety of PG's, Tx, and LT's are produced.

PG's serve to modulate (not necessarily to suppress) the immune response, and LT's serve to increase it. Thromboxane serves to cause platelet aggregation and vasoconstriction. Generally, a more potent PG response means greater immune suppression; a more potent LT response means greater inflammation; and a more potent thromboxane response means greater platelet "stickiness" and risk of thrombosis. It appears that n-3 supplementation improves the condition of people suffering from inflammatory diseases, including Behcet's. A look at some of the studies done on the effects of n-3 supplementation will illuminate the bio-chemical processes involved.

Effect of Dietary Lipids on the Cycloxygenase and 5-Lipoxygenase Pathways

"In general, as the n-6 content increases, and the n-6/n-3 PUFA ratio increases over 1, the more dienoic eicosanoids are produced within and released from the cell membrane. These two series of eicosanoids have different potency. The eicosapentanoic acid (20:5n-3) products are less inflammatory than those of linoleic acid (18:2n-6). A relative excess of linoleic acid substrate stimulates prostaglandin E2 production, which decreases the ability of cytokines to stimulate interleukin-2 synthesis by endothelial cells, and suppresses T-cell proliferative responses in response to lectin and specific antigen has been hypothesized that n-3 PUFA would decrease macrophage prostaglandin E2 and cytokine release and stimulate T-cell proliferative responses..." (Cerra 1991)

A study done by the New England Medical Center Hospital in cooperation with the Tufts University School of Medicine, Harvard Medical School and others (Endres et al 1989), demonstrated a significant decrease in the synthesis of IL-1 and TNF by mononuclear cells by dietary supplementation with n-3 fatty acids. Subjects added 18 grams of marine lipid concentrate, Max-EPA, to their daily diets, which otherwise remained unchanged. Each gram of Max-EPA was found to consist of 153 mg of EPA and 103 mg of DHA, so they were receiving 2.75 grams of EPA and 1.85 grams of DHA daily. The composition of mononuclear-cell phospholipid fatty acids in mononuclear cell membranes was monitored and a significant increase in EPA with a concomitant decrease in arachidonic acid was found after six weeks. This effect continued to ten weeks after cessation of treatment. Twenty weeks after supplementation ended, both EPA and AA had returned to pre- supplementation levels. A 32% decrease in IL-1a production was shown after six weeks, increasing to 39% at ten weeks; for IL-1b the decrease was 43% and 61%, respectively. TNF dropped 22% after six weeks, 40% after ten weeks. Within 20 weeks of cessation of treatment, all levels returned to pre-treatment levels.

PGE-2 synthesis in mononuclear cells stimulated by S. epidermidis decreased 51% after six weeks and slowly returned after cessation of treatment. The chemotactic responses of PMN after six weeks were suppressed by 25%.

The authors concluded that dietary supplementation with n-3 fatty acids reduces the amount of inducible production of IL-1 and TNF by mononuclear cells in vitro. The reduced production of these may contribute to the decreased inflammatory responses reported in patients receiving n-3 supplementation. Also noted was the persistence of effects for at least ten weeks after supplementation ended. This correlates with a study of n-3 effect on rheumatoid arthritis in which LTB-4 generation remained below baseline levels for as long as 18 weeks after supplementation was stopped.

While the authors felt that the mechanism underlying the effect remains unknown, they suggest that alterations in the type of AA metabolites produced during stimulation of the mononuclear cells may explain in part the decreased production. "A possible mechanism for decreased IL-1 production is decreased synthesis of LTB-4 and generation of the biologically less active metabolite LTB-5 from EPA."

The authors of an earlier study (Lee et al 1985) had already concluded that fish-oil derived fatty acids may have anti-inflammatory effects by inhibiting the 5-lipoxygenase pathway in neutrophils and monocytes and inhibiting the LTB-4 mediated functions of neutrophils. The prostaglandine endoperoxides and thromboxane A3 derived from EPA "have attenuated platelet-aggregating ability as compared with the AA- derived products." DHA had little effect, but EPA markedly down regulates the elaboration of LTB-4 and yields a structurally analogous product, LTB-5, with markedly attenuated chemotactic and aggregating activities for human neutrophils. In fact, LTB-5 is ten to thirty times less active than LTB-4 as an attractant for human neutrophils (Shils et al 1994).

The subjects in this earlier study also took Max-EPA supplements, providing 3.2 g of EPA and 2.2 g of DHA daily. After three weeks there was no difference in products generated, but after six weeks the average production of LTB-4, 6-trans-leukotriene B-4 diastereoisomers, and 5-HETE was decreased by 48%. Before the diet began, immunoreactive LTB-5 and 5-HEPE were not generated; levels were increased at three weeks. The chemotaxis and adherence of neutrophils was attenuated after six weeks on the diet. "It is likely that the decrease in 5-lipoxygenase products from ionophore-stimulated neutrophils after six weeks of the diet was due to impairment of the total release of AA and possibly of AA from a phospholipid pool preferentially involved in 5-lipoxygenation."

Neutrophil chemotactic response to LTB-4 decreased by 70%; capacity to adhere to LTB-4-pretreated endothelial-cell monolayers was also significantly reduced.

The authors noted that in two previous studies, LTB-4 production was not suppressed, but added that the subjects were not studied for six weeks, nor were they assessed for all 5-lipoxygenase products, or for effect on neutrophil function.

A study done on the effect of dietary fish oil on renal function and rejection in cyclosporine-treated recipients of renal transplants (Homan van der Heide 1993) showed a beneficial effect. This article noted that, independently of cyclosporine, fish oils reduce the generation of cytokines such as IL-1, IL-2, IL-6 and TNF via a change in the leukotriene profile.

"One of the mechanisms by which steroids prevent cell infiltration is related to the inhibition of phospholipase A2 and the consequent mobilization of free arachidonic acid resulting in inhibition of cyclooxygenase and lipoxygenase products. The discovery of specific lipoxygenase inhibitors would complement the activities of existing NSAIDS, and by inhibiting both pathways an effective inhibition of the cellular and edematous phases of the inflammatory response will be expected. These strategies together with LTB-4 receptor antagonists, IL-1 and TNF production inhibitors of adhesion molecule interactions should provide sufficient therapeutic advances for treatment of such diseases as rheumatoid arthritis, psoriasis, asthma, acute respiratory distress syndrome, inflammatory bowel disease, and myocardial reperfusion injury, among others."

n-3 fatty acids from fish oils and flax oil could be what they're looking for.

Gurer et al (1991) studied the effects of colchicine, which has been used effectively against Behcet's mucocutaneous symptoms, on levels of PGE-2 and LTC-4 in Behcet's patients. Levels of both eicosanoids decreased significantly with colchicine treatment. As the subjects showed improvement in symptoms as well, it was concluded that colchicine acts to reduce inflammation by affecting both the cycloxygenase and lipoxygenase pathways and reduces neutrophil chemotaxis. However, an alternative explanation offered was that colchicine inhibits inflammation by a different mechanism and that as a result of reduced inflammation the levels of AA metabolites fell, then inhibiting PML chemotaxis and resulting in improvement of the lesions.

The Role of Cycloxygenase Products, esp. PGE-2

In Vascular Permeability:

"Most of the cycloxygenase products contribute to the vascular phase of inflammation. For example, PGE-2, PGD-2, and PGI-2 cause vasodilation but do not increase vascular permeability by themselves; however, they synergize with the proinflammatory mediators leukotrienes, bradykinin, and serotonin to increase vascular permeability. Thromboxane A2 induces platelet aggregation and release of vasoactive platelet mediators."

The Role of 5-Lipoxygenase Products

In Vascular Permeability:

"The contribution of lipoxygenase products to inflammation is characterized by the ability of the peptidoleukotrienes to increase vascular permeability and bronchial constriction."

In Chemotaxis: "LTB-4 is a potent chemotactic agent for neutrophils, eosinophils, and monocytes and promotes the secretion of reactive oxygen species and hydrolytic enzymes from neutrophils. Therefore, LTB-4 is believed to play a critical role in the recruitment and activation of inflammatory cells at the site of tissue injury."

"An inhibitor of 5-lipoxygenase might be particularly useful (against pulmonary inflammation), since it would block the formation of LTB-4, which may be important as a chemotactic attractant of neutrophils, as well as bronchospastic sulfidopeptide leukotrienes. Several drugs have been developed which inhibit 5-LO and most of these have proved to be anti-oxidants, so it may be difficult to be certain about whether any beneficial effect is due to enzyme (LTB-4) inhibition." (Bray & Anderson 1991,p.626)

Decreased Superoxide Production Associated with n-3 Competition

Superoxide production with 5HPETE would be inhibited by n-3 fatty acid competition in the lipoxygenase pathway, being replaced by 5HPEPE in that stage of the process. In the process of arachidonic acid being converted to ann endoperoxide (and then to more stable eicosanoids), oxygen is reduced to superoxide (O2-). "While the amount of O2- produced is small, there is some evidence that this may be biologically important, although, in the neutrophil, blocking of cycloxygenase does not measurably affect the total amount of 02- generated following contact with an antagonist. This mechanism may be more important in endothelial cells in which prostacyclin [PGI-2] production can lead to O2- formation."(Bray 1991). Vascular endothelial cells and small muscle cells convert PGH-2, which is a cycloxygenase pathway pre-cursor to PGE-2 as well, to PGI-2, and PGI-2 is responsible for arachidonic-induced vasodilation and antiaggregating influence on platelets.

Researchers at the University of Massachusettes (Weiner 1988), assessing the effect of dietary n-3 fatty acid supplementation on monocyte inflammatory potential in 9 healthy volunteers, did report that six weeks of dietary supplementation with 3.6 grams of EPA and 2.4 g of DHA decreased superoxide production by circulating monocytes in all subjects; the mean reduction was 59%. Lymphocyte arachidonic acid levels declined by 36%, while EPA increased 237%. Could this have an effect on BD?

As mentioned earlier, Pronai et al (1990) found no difference in the superoxide scavenging activity of mononuclear cells when comparing subjects with BD and RA with each other and with healthy controls. In following their hypothesis of SOD deactivation by O2-, this would indicate that in BD and RA, superoxide production in mononuclear cells is normal. Yet Weiner showed that n-3 supplementation cuts superoxide production by monocytes in healthy subjects, probably via decreased chemotaxis/phagocytosis. It would be interesting to see if what happens to superoxide production by mononuclear cells in patients with BD given supplemental n-3.


Cells protect themselves from autooxidative damage in several ways. These include the antioxidants, either the enzymatic or preventive type exemplified by superoxide dismutase, catalase, and peroxidase enzymes, which neutralize oxidants by decomposition to terminate free radical formationm, and non-enzymatic, chain-breaking or scavenger antioxidants, the more important of which are ascorbate, a-tocopherol, and glutathione. The enzymatics are the first line of defense, but significant amounts of reactive metabolites escape inactivation and require the action of scavenger antioxidants.

It has been found that in trauma patients a-tocopherol and ascorbate are considerably diminished, while glutathione remains unchanged (Madazero et al 1990). In the recovery period, levels of ascorbic acid and a-tocopherol may remain inadequate, but PMN function is normal. Additional injury or systemic infections may, however, make PMN more vulnerable to their own oxygen metabolites.

Effect of Specific Nutrients on Immune Response and Oxygen Radicals

Note: The following is not an exhaustive description of every process that each nutrient has been found to be involved in or may be involved in.

Vitamin A:

Kinsella and Lokesh (1990): "Enhances immune responsiveness via increased macrophage cytotoxicity and cytotoxic T-cell activity". Vitamin A is also an anti-oxidant.

Vitamin B1:

"Reports suggest that thiamin reverses inhibition of neutrophil migration caused by the peroxidase H2O2-Halide system. These observations suggest that thiamin has an antioxidant effect." (Shils 1994) I don't quite understand what they mean by this. However, note that dapsone, a drug sometimes used against Behcet's, may operate at least partly by interfering with the myeloperoxidase-H2O2-halide-mediated cytotoxic system within neutrophils.

Vitamin C:

For protection against the oxidants that they produce, neutrophils acquire a high level of intracellular ascorbic acid by oxidizing extracellular ascorbic acid to a form which can cross the cell membrane and be reduced to ascorbic acid again very quickly (NR 1993). The build-up of a protective level of ascorbic acid in neutrophils, say Washko et al 1993, is achieved by what is termed "antioxidant recycling. It is in the course of scavenging oxidants that ascorbic acid uptake increases.

"Ascorbic acid can react with and scavenge many types of free radicals, including singlet oxygen, superoxide, and hydroxy radicals. In addition, ascorbate can regenerate the reduced form of a-tocopherol, perhaps accounting for observed sparing effects of these vitamins."(Padh 1991)

In fact, studies indicate that the antioxidant role may be the prime function of ascorbate. (Padh 1991)

Madazero (1990) and others report that there is a decreased ascorbate level in tissue fluids and cells in postinjury animals and in humans. As previously mentioned, trauma seems to cause PMN dysfunction and autooxidation, and it has been found that it is the loss of ascorbate and a-tocopherol just when these cells need them most is responsible.

If the uptake of extracellular ascorbic acid increases particularly during times of oxidant scavenging, which would be when PMN's are most active in producing oxidants, then this would explain the depletion of and possibly indicate a need for supplementation of ascorbate and a-tocopherol. According to Madazero et al, however, it is not known whether replacement therapy with ascorbic acid and a- tocopherol at amounts enough to replenish serum concentrations to normal will reverse or hasten the resolution of PMN dysfunction in the trauma patients they were concerned with.

As mentioned earlier, vitamin C has a sparing effect on a- tocopherol. It reacts with the intermediate oxidation by-products (tocopherol radicals) to regenerate the reduced tocopherol. "The ascorbate, in turn, can be regenerated from the resulting ascorbate radical by NADH in the presence of NADH reductase. Thus, a-tocopherol and ascorbic acid can be expected to be synergistic and the combination is a potent protective system against oxidants."(Madazero)

Vitamin C is also reported to inactive and neutralize histamine (Padh 1991). This would aid in preventing vasodilation and deposit of immune complexes.

Vitamin E:

"The lipid solubility and the strategic location of a-tocopherol, being present in high concentrations in all lipid membranes, position this nutrient as a critical defensive arm against cellular oxidative attack, particularly against membrane lipid peroxidation and loss of normal membrane integrity."(Madazero et al 1991).

Some studies have indicated that vitamin E has a role in regulating the cycloxygenase pathway and therefore affects the production of PGE2. One study, however, showed that vitamin E supplementation had no effect on human platelet function, arachidonic acid metabolism, and plasma prostacyclin levels in healthy human subjects (Stampfer 1988).

20 adults participating in a randomized, placebo-controlled, double-blind trial received 800 IU daily for five weeks. Despite marked increases in plasma and erythrocyte vitamin E levels, there were no significant differences in platelet aggregation, the cycloxygenase products MDA, thromboxane B2, and HHT, the lipoxygenase product 12-HETE, or prostacyclin (PGI-2). An earlier study cited by Stampfer (Swartz et al 1985) had indicated that vitamin E supplements causes a marked decline in prostacyclin levels in healthy adults. In both studies a degradation product of PGI-2, circulating PGF-1a, was measured.

Vitamin E is also said to increase IL-2 formation and reduce antigen-induced suppression of NKC (Natural Killer Cell) activity. In one study, a decrease in IL-6 production was seen. It is not believed to affect IL-1 production. While thought by some to depress PGE2 synthesis, E has also depressed mitogen-induced lymphocyte proliferation.

Selenium: Selenium forms a part of glutathione peroxidase, an enzyme in the defense against oxidant damage. Selenium may also decrease platelet aggregation. Lower levels of selenium have been linked to incidence of cancer, particularly among those with low blood vitamin E and A levels. Selenium has been found to have anti-inflammatory properties, including those involving auto-immune disease. Animals given supplemental selenium have shown increased phagocytic activity. Animal studies have also demonstrated large increases in antibody production following administration of selenium, including up to thirtyfold increases when in combination with vitamin E. Mechanisms remain obscure. (Sheldon 1990)

Superoxide Dismutase:

This is produced by the body and is a tremendously potent antioxidant. Supplemental SOD (in injectible form) has had significant impact on the autoimmune disease scleroderma, in healing radiation damage, and "excellent" results have been reported in cases of Crohn's disease, Behcet's disease, Raynaud's syndrome, Kawasaki disease, and unresponsive anemia.


See description above.

Glutathione (GSH):

A key component of glutathione peroxidase. As mentioned earlier, glutathione is also a key anti-oxidant in its own right. It is produced by the body, but several methods of increasing cellular GSH levels have been tried. Administration of GSH itself causes only small increases in cellular GSH levels. There is a form which is easily transportable across cell membranes, glutathione ethyl ester, and it has been shown in animals and in vitro tests to successfully raise intracellular levels of GSH.

Copper, Zinc:

Components of superoxide dismutase.

Overall Effects Sought

The overall goal is to reduce tissue damage. If the body were able to successfully deal with the antigen in the earliest stage of the disease, then the patient would be cured. However, until the ultimate cause is discovered, the focus of therapy will be on phases II and III. Overall, we will seek to increase the body's ability to clear circulating immune complexes by enhancing phagocytic efficiency; we will seek to prevent or delay the deposition of circulating immune complexes by reducing vasopermeability; we will seek to reduce the chemotaxis of polymorphonuclear leukocytes (neutrophils) in inflammed tissues; and we will seek to enhance the two lines of defense against autooxidation by enhancing the body's production of enzymatic antioxidants like superoxide dismutase, catalase, and peroxidase and augmenting the supply of nonenzymatic antioxidants like ascorbate, a-tocopherol, and glutathione. PMN's also must be protected from auto-oxidation.

We wish to achieve these without exacerbating inflammation or weakening the body's defenses against other diseases. We also wish to find an effective solution which may be achieved through dietary means in addition to or instead of supplementation or the pharmaco- nutritional approach.

Effect Sought on Pre-active Phase

In the pre-active phase, one would want to ensure that the initial response was sufficient to prevent release of antigen into the circulation.

Effect Sought on Phase II

Here the objective is to get the circulating immune complexes cleared and to prevent their deposition in tissues. Chemotaxis and phagocytosis must be unblocked. An increase in antibody (Ig) production might help; greater NK cell effectiveness, requiring that those NK cells released are more mature, might help. An improved T-cell response might help.

It would probably help to delay the deposition of CIC's in tissues by reducing vasopermeability.

Effect Sought on Phase III

If circulating immune complexes become deposited, we wish to minimize the tissue damage caused by the infiltration of neutrophils (PMNL's). This may be accomplished by ensuring that there is an adequate level of anti-oxidant production and supply for both the cells around the infiltration and for the neutrophils themselves.

Plan of Action

(Note: "Ch." refers to the person for whom this program was intended).

The following is the recommended program of nutritional supplementation. The only dietary changes recommended at this time will be an increase in fresh fruits and vegetables.

Patients with particular medical conditions should consult physicans before engaging in supplementary nutritional programs, even though physicans may be ill-informed on the subject in general.

Capsules afford a higher absorbtion rate than tablets, generally.

Some of the following may cause false laboratory readings.

If any adverse signs are experienced, the person on the program should stop and steps should be taken to isolate the problem. A dosage may have to be adjusted, or a particular supplement taken in another form or eliminated from the program.

Because this is not a controlled study, but simply an educated attempt to help Ch. stop Behcet's effect on her body, we won't really know which element is responsible for helping if positive results are obtained. The controlled studies are for others to perform; we just want to see improvement.

1. n-3 fatty acids:

Some promotional material on flax oil which I've read says we need at least 1-2% of daily calories from n-6; the optimum is 5-10%. It also says we need at least 2% of daily calories (1 tsp) of n-3 LNA per day. The ratio of n-3 to n-6 should be 1:4 at the lowest. Greenland Eskimos have a 1:1 ratio. The usual for Americans, according to the material, is 1:20. Simopoulos (see below) says it's 1:10-11.

Galli and Simopoulos (1988) summarized the results of their roundtable on n-3 fatty acids with the following recommendations:

1. Total fat intake should be <30% of daily calories.

2. Saturated fat intake should be <10% of daily calories.

3. The total polyunsaturated fat shuld be a mixture of n-6 plus n-3 polyunsaturates.

4. Research suggests that as a minimum, linoleic acid (n-6) should account for 3% of daily calories. As a minimum, linolenic acid (n-3) should account for 0.25 to 0.54% of calories. EPA plus DHA should account for 0.15% of calories.

North American adults, according to Galli and Simopoulos, exceed the maximum saturated fat intake by 50%, get 18% of calories from monounsaturated fatty acids, and get 7% from polyunsaturated fatty acids. They get 0.7% of calories from linolenic acid (n-3), 0.3% from EPA, and 0.3% of calories from DHA.

The current n-6/n-3 ratio is said to be 9:1, far too high, and there is a deficiency of EPA and DHA.

Galli and Simopoulos recommend that in normal healthy adults free from medical disorders (which is not Ch.), and assuming 2600 calories/day, 14 g. per day, or 4.8% of calories should come from linoleic acid (n-6); 3 g. per day or 1% of calories, should come from linolenic acid (n-3); and EPA plus DHA should account for .8 g/day (800 mg), or .27% of calories. The total PUFA intake is 18 g/day, or 6-7% of calories. The n-6/n-3 ratio in their plan is 4:1.

They conclude that the saturated fatty acids should account for 6-7% of calories, and that monounsaturated fatty acids (mainly as oleic acid) may account for 12-14% of calories.

In the studies of the effect of EPA and DHA cited earlier, subjects received 18 capsules of Max-EPA daily. This provides 18 grams of fish oil concentrate "providing" 3.2 grams of EPA and 2.2 grams of DHA. This means that each capsule provided 177 mg of EPA and 120 mg of DHA. In the Endres et al study, each capsule was found to contain 153 mg of EPA and 103 mg of

DHA. Now, one tablespoon of Dale Alexander Emulsified Cod Liver Oil, standard form (de-vitaminized or regular) supplies 460-552 mg of EPA and 420-500 mg of DHA. This means that to obtain the therapeutic level of EPA (3.2 grams), Ch. would have to take about six tablespoons per day. This six tablespoons of non-de-vitaminized emulsified cod liver oil provides 720 calories, which would be approximately 36 percent of Ch. dietary intake (assumed for the moment to be 2000 per day).

Since we wish to avoid causing a vitamin A and vitamin D overdose, and since we wish to reduce the amount of oil that needs to be ingested, the de-vitaminized and more highly concentrated Dale Alexander Emulsified Omega-3 Fish Oil Concentrate would be much better. Each tablespoon contains 1024 mg of EPA and 712 mg of DHA, so Ch. would take three tablespoons per day. Caloric content would be 360 calories, meaning a-Linolenic Acid is accounting for 18% of daily caloric intake.

The alternative to cod liver oil as a source of n-3 is flax oil. The type I sampled was called Veg-Omega 3. Each tablespoon provides 5600-8500 mg of a-Linolenic acid, a much higher content than cod liver oil, but no free EPA or DHA. Someone at the company said that she'd heard that the conversion rate in the body was 20%. Assuming this to be true, then this tablespoon provides 1120-1700 mg of EPA, which is 37% to 57% of what we want. So, Ch. should take about 2 tablespoons per day. This provides 240 calories. Flax oil, 57% n-3, also contains 16% n-6 and 18% n-9 (oleic acid). So, the recommendation in this plan is for Ch. either to take 2 tablespoons of the flax oil available in the health food stores or three tablespoons of the de-vitaminized, emulsified Dale Alexander Fish Oil Concentrate (Twinlab) for at least eight to ten weeks. There should be no adverse side effects. If her symptoms disappear, then she should reduce this to a maintenance level of 1 tablespoon per day (flax oil) or 1.5 - 2 tablespoons per day (Fish Oil Concentrate) and see if the symptoms return. If the oil is reponsible for alleviating the symptoms, then they will probably return if she stops taking the oil completely, as was shown in the studies cited earlier.

A minimum amount of n-6 linoleic acid is required in the diet. Cod liver oil supplies none, while flax oil provides some, in the ratio of n-3/n-6 ratio of 3.5:1. Considering that the typical American diet contains much more n-6 linoleic acid than n-3, in the form of vegetable seed oils (safflower oil, sunflower oil, corn oil, sesame oil, peanut oil, almond oil, and olive oil), I don't think we have to be concerned about any harm from possibly reversing the ratio. But without a study of Ch. diet, it's hard to determine just what the ratio will be.

Sheldon (1990) recommends that cod liver oil should be taken with 30- 200 IU's of vitamin E and 50-200 micrograms of selenium daily, though not necessarily at the same time. Also, those predisposed to easy bleeding or hemmorhage should use fish oil only with their physician's approval.

2. Vitamin A: 25,000 IU per day in the form of beta carotene (pro- vitamin A), which is non-toxic and is converted into Vitamin A as the body requires it. However, 5000 IU of Vitamin A itself should be added, because it is needed to stimulate the conversion of beta carotene to A.

Capsules should be swallowed with a full glass of liquid, and taken with or immediately after food.

Note that antacids decrease the absorbtion of vitamin A, D, E, and K (fat-soluble vitamins).

3. Vitamin C: 1000-1500 mg. per day, in the form of calcium ascorbate. This form of Vitamin C is buffered and should minimize any stomach irritation. It is acknowledged that we will probably have an absorbtion rate of 50% at 1500 mg (750 mg absorbed), but any excess is excreted in urine and we want to ensure serum saturation.

In capsule form, swallow whole with a full glass of liquid. Take with or immediately after food to decrease stomach irritation. In an oral solution (recommended here), dilute with liquid and take with meals or 1 to 1-1/2 hours after meals.

4. Vitamin E: 200-400 IU of alpha-tocopherol per day. If there is a possibility of decreased lipid absorbtion, a dry form should be used. Swallow whole with a full glass of liquid and take with or immediately after food to decrease stomach irritation.

5. Selenium: 200 micrograms of an organic form of selenium (seleno-methionine). Vitamin C may decrease selenium absorbtion if taken with an inorganic form of selenium (like sodium selenite). Take with full glass of liquid; take with meals or 1 to 1-1/2 hours after meals.

6- Superoxide Dismutase and Catalase

The best success has been reported with injections of liposomal-encapsulated SOD. But due to the cost and our desire to avoid injections, we have to look to an oral source. But oral supplements are said to be completely destroyed in the intestines. There is a sub-lingual lozenge available, which would send free SOD more directly into the blood stream, but the dosage is very low.

There is a product manufactured by a company called Biotec which is supposed to increase the body's production of SOD, catalase, and GSH-Px. The tablets, called "Cell-Guard", contain a concentrate of genetically-engineered wheat sprouts, and are marketed as the best alternative to injections. Literature from Biotec describes the results of several studies on which they base their claims. The first is a study of the effect of the Biotec tablets on the erythrocyte SOD levels of ten healthy, elderly subjects. After about two weeks, the subjects showed an average 230% increase in erythrocyte SOD levels; the minimum increase was 32%, the greatest 730%. Six tablets were taken daily upon rising, one hour before breakfast, for the first two weeks, three daily for the second two weeks.

Another study showed increases in serum SOD levels averaging 40%, increase in catalase 60%, and serum glutathione peroxidase up 78% in the age range 41-50. Placebos showed virtually no increase. The company literature also cited more subjective studies indicating reduction of pain and increase in overall feeling of well-being among almost all customers surveyed by participating physicians.

Since we have no other good oral means of improving SOD levels and catalase levels, this "Cell-Guard" product seems worth trying. Take according to directions, which is upon waking and an hour before eating the first meal. Eight glasses of water per day is important.

7. Glutathione: The only form that appears readily available is a 100 or 250 mg. capsule containing gamma-L-Glutamyl-L-Cysteinyl-Glycine. I don't know if this is the glutathione precursor ester that is well absorbed by cells. It is manufactured by Twinlab.

8. B-Complex, Special note on B-12 and Folic Acid: I am including a B-complex supplement in the program. Of particular interest in terms of immune response is thiamin (B-1), but B-12 and folic acid could be important in Ch.'s case for the reasons given below.

I am particularly interested in folic acid because of the coincidence of possible anemia and gastro-intestinal disturbance in Ch. Both of these can be caused by low folic acid levels, in turn caused by poor diet and/or anorexia. I also came across a photograph in Cawson et al (1989) of an oral ulceration, and the caption said "Folic acid deficiency. This patient had megaloblastaic anemia due to folic acid deficiency secondary to prolonged treatment with phenytoin. The main complaint in this case was recurrent oral and genital ulceration (Behcet's syndrome), which responded dramatically when folic acid was given." Now, it seems that the treatment here was for aphthous ulcer, not really complete Behcet's disease. But the connections are too strong to ignore. Folic acid is included in Ch.'s program for this reason.

Folic acid deficiency can also significantly impair neutrophil phagocytosis, decrease T-cell cycotoxic function, and cause delayed hypersensitivity reactions, all of which are found in Behcet's.

Folic acid: >100 micrograms per day is desirable in hypermetabolic conditions or with hemolytic anemia. 500-1000 micrograms is given to stop deficiency, and the maintenance dosage is 100 micrograms daily for 1-4 months. One fresh fruit or vegetable per day can replace this.

Oral folic acid supplements of 350 mg/day or more may reduce zinc absorbtion.

Because B-12 deficiency can masquerade as folic acid deficiency, and vice-versa, and since B-12 is important in preventing anemia, both should be taken and both are included in the B-complex formula.

The recommended B-complex formula is either the Twinlab B-50 caps or the Nature's Life B-50 "Special" capsules. The latter is much less expensive and provides the same level of vitamins, except slightly less B-5 and 800 micrograms of folic acid vs. 400 in the Twinlabs. This is actually more folic acid than we're looking for, so the Twinlabs or some alternative might be better.

9. Iron: Important in the immune response, but in our case is needed because Ch. may be anemic. The best supplements in terms of absorbtion are, in order of greatest to lowest absorbability, ferrous succinate, ferrous fumarate, f. glycine sulphate, f. glutamate, f. gluconate, f. citrate, f. tartrate, and there are a few more which I won't mention. The desired absorbtion is 40-50 mg, which can be achieved with a dosage of 200-240 mg. of supplement. An enteric- coated or time-release capsule or tablet should not be used.

If Ch. has an iron malabsorbtion problem, oral supplements can't help.

10. Copper: 3-6 mg per day. Copper is a key component of SOD, but one of the main reasons to include it in the program is that high vitamin C intake may produce copper deficiency and cause the oxidase activity of cerruloplasmin, which metabolizes iron, to be impaired. We don't want to promote anemia. However, excessive copper can also produce anemia.

Excessive zinc intake can also cause a copper deficiency, although the amounts taken will be low enough to prevent this (see below).

The chelated version should be better absorbed.

11. Zinc: A component of SOD. No more than 16 mg per day. Supplements as low as 25 mg can cause copper deficiency, so we have a margin of safety. 12 mg is the RDA. If Ch. takes folic acid in excess of 350 mg/day, it could lead to a decrease in zinc absorbtion.


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