Ameliorating Role Exerted by Al-Hijamah in Autoimmune Diseases: Effect on Serum Autoantibodies and Inflammatory Mediators

Autoimmune diseases have common properties characterized by abnormal blood chemistry with high serum autoimmune antibodies, and inflammatory mediators. Those causative pathological substances (CPS) cannot be excreted by physiological mechanisms. Current treatments for autoimmune diseases involve steroids, cytotoxic drugs, plasmapheresis and monoclonal antibodies. Wet cupping therapy (WCT) of prophetic medicine is called Al-hijamah that treats numerous diseases having different etiology and pathogenesis via a pressure-dependent and size-dependent non-specific filtration then excretion of CPS causing clearance of blood and interstitial fluids. Al-hijamah clears blood passing through the fenestrated skin capillaries. Medical bases of Al-hijamah were reported in the evidence-based Taibah mechanism (Taibah theory). Al-hijamah was reported to be an excellent treatment for rheumatoid arthritis that improved patients’ blood chemistry and induced significant clinical improvement and pharmacological potentiation. Al-hijamah improved the natural immunity and suppressed the pathological immunity through decreasing the serum level of autoantibodies, inflammatory mediators, and serum ferritin (a key player in autoimmunity). Al-hijamah reduced significantly pain severity, number of swollen joints and disease activity with no significant side effects. Main steps of Al-hijamah are skin suction (cupping), scarification (sharatmihjam in Arabic) and second suction (triple S technique) that is better therapeutically than the traditional WCT (double S technique). Whenever an excess noxious substance is to be removed from patients' blood and interstitial fluids, Al-hijamah is indicated.Shartatmihjam is a curative treatment in prophetic teachings according to the prophetic hadeeth: "Cure is in three: in shartatmihjam, oral honey and cauterization. I do not recommend my nation to cauterize".Al-hijamah may have better therapeutic benefits than plasmapheresis. Al-hijamah may be promising in treating autoimmune diseases as a sole treatment or adjuvant treatment.


Introduction
The mere presence of autoantibodies is sufficient to establish the diagnosis of autoimmune diseases, which requires more clinical and additional laboratory evaluation. (1-3) In general, B-cell stimulation is dependent upon help gained from T cells.Multiple mechanisms exist to regulate the function of self-recognizing T lymphocytes including peripheral deletion mechanisms, induction of anergy and active suppression of self-reacting lymphocytes.
Immunopathology of autoimmune diseases involves participation of autoantibodies, complement activation and disorders related to cell-mediated and humoral immunity. (4)utoimmune diseases are characterized by an abnormal blood chemistry in which there are high serum levels of auto-antibodies, immune complexes, inflammatory mediators, inflammatory cytokines, soluble cytokine receptors, prostaglandins and others.
(4) There is no physiological mechanism to clear serum and/or interstitial fluids from these abnormal constituents.Also, there is no pharmacological treatment to restore the normal blood chemistry or homeostasis through excretion of the above-mentioned pathological substances.Current pharmacological treatments of autoimmune diseases may suppress the inflammatory and autoimmune reactions but do not clear patient's serum or interstitial fluids from the above-mentioned causative pathological substances (CPS).Such pharmacological treatments include steroids, (5)   potent anti-inflammatory drugs, cytotoxic drugs, (6) disease-modifying anti-rheumatic drugs (7) and monoclonal antibodies directed against target cells or autoimmune antibodies. (8)Numerous drug side effects are encountered in pharmacological treatments used for treating autoimmune diseases e.g.non-steroidal anti-inflammatory drugs induce gastritis, gastric ulcers and toxicities at high doses, while prolonged steroid therapy causes osteoporosis, hypertension, steroid diabetes, gastric ulcers and steroid dependence. (5)Cytotoxic drugs have many unavoidable serious side effects, which may necessitate drug discontinuation.(6, 9)   Non-specific immuno-suppression may help in treatment of all autoimmune disorders, but adverse side-effects (acquired immunodeficiency diseases, cancer and drug toxicity) can harm the patients rather than benefiting them. (4,10) toimmune diseases may be organ specific (e.g.Hashimoto's thyroiditis), a mixture of organ specific and systemic symptoms (e.g.rheumatoid arthritis, RA) or diseases with nonorgan specific autoimmune reactivity (e.g.systemic lupus erythematosus, SLE).
(3, 4) Al-hijamah (cupping therapy of prophetic medicine) is a well-known treatment modality in the Arabic medical literature in Arabic countries as it is a highly recommended treatment in prophetic medicine.(11-12)   In this article, we will review here important aspects regarding autoimmune diseases, Alhijamah as a promising treatment, scientific bases beyond Al-hijamah and therapeutic roles of Al-hijamah in treating autoimmune diseases that may be an adjuvant treatment to current treatment modalities for treating autoimmune diseases. (12)

Immunological tolerance (table 1):
The autoreactive B and T-lymphocytes that are sensitized against self-antigens are key players in the pathogenesis of autoimmunity.Immunological tolerance refers to immunological unresponsiveness towards one's own self antigens.It is also called autotolerance and is regulated through many immunological mechanisms in both B and T lymphocytes that prevent them from attacking self-antigens.
(1-4) Loss of self-tolerance leads to autoimmunity.Mechanisms for tolerance induction include deletion of autoreactive Tlymphocytes (activation-induced cell death), suppression and deletion of autoreactive Blymphocytes in the bone marrow, lack of T-cell help for B-cell activation, removal of necessary signals for induction of autoreactivity, absence of appropriate major histocompatibility complex (MHC) molecules for antigen presentation and absence of co-stimulatory molecules.

Causes of autoimmunity (table 1):
Causes of autoimmunity are wide and diverse.Autoimmunity occurs upon lack of immunological tolerance leading to attack of self-antigens by the own immune system.Autoimmunity has a familial predisposition and is enhanced with infectious microbes producing peptide antigens similar in structure to self-antigens (molecular mimicry), where bacterial peptides cross-react with self-antigens leading to activation of the immune system. (15)oreover, drugs, chemicals bacterial infections and viral infections may cause alteration of self-antigens e.g.tissue proteins, which may affect the behavior of the immune system towards these tissue proteins.Infection with streptococci may cause cross-reactivity of the immune system towards self-antigens where an immunological reaction occurs against the protein of the heart valves resulting in the pathogenesis of rheumatic fever.(16)   Similar to that is the appearance of new antigens that are similar to tissue antigens by the effect of viral infections or chemical substances (16) leading to self-attack by one's immunological system (3,13,17) e.g.short amino acid sequences in myelin basic protein are identical to sequences in an adenovirus (type-2) protein, while other sequences are homologous to sequences in hepatitis B protein.Altered antigen presentation refers to the presentation of antigens together with MHC by cells not normally expressing MHC.(4, 18-20)   This may participate in induction of autoimmunity.
It is noteworthy that defects in the normal regulation of lymphocyte development and activation e.g.defects predisposing to low regulatory T-helper-2, cytokine production and lack of induction of apoptosis to autoreactive Tcell clones "bystanders" during normal immunological responses to infection may break the immunological tolerance leading to autoimmunity.
(4, 21)   Etiology of autoimmune diseases includes also genetic defects leading to defects in lymphocyte regulation, loss of stimuli causing apoptosis, development of antigen-related mechanisms and effects of some hormones. (22- 23)The ratio of females to males presenting with Hashimoto's thyroiditis is 50:1 and 10:1 in SLE, while the male to female ratio is 9:1 in ankylosing spondylitis. (3)(4)24)uperantigen-related mechanisms may cause autoimmunity i.e. superantigens activate entire sets of T cells whose T-cell receptors share a common variable region segment.This occurs typically in the T-cell receptor-β chain leading to sensitization of T cells (table 1). (9,25) 8)

Loss of apoptotic stimuli causing increased proliferation of activated clones of autoreactive cells in the immune system. 3. Superantigen-related mechanisms causing increased proliferation of activated clones of autoreactive T cells in the immune system. 4. Antigen-related mechanisms:
-Molecular mimcry (similarities between self-antigens and foreign antigens) -Cross-reaction (between self-antigens and foreign antigens) -Altered antigen presentation (causes a change in immunity against self-antigens) -Loss of sequsestration (some antigens become in contact with the immune system e.g.eye lens)

Immunological tolerance (Protects against development of autoimmune diseases)
A. Central tolerance 1.In the thymus Termed negative autoselection --Involves deletion of autoreactive T-cells -Occurs when T-cell receptors mistakenly bind to self-antigens and become autoreactive.(13, 29)   In type III-induced autoimmunity (immune complex-mediated reactions), antigens and autoantibodies exist and escape from removal by the reticuloendothelial cells.This leads to complement activation, mast cell degranulation, histamine secretion and platelet aggregation (microthrombi formation).Examples of type III-induced autoimmunity include SLE and rheumatoid arthritis (RA).)13) In type IV-induced autoimmunity (delayed type hypersensitivity reactions), tissue damage occurs as a consequence of sensitized T lymphocyte activation leading to macrophage and lymphocytes activation with production of hydrolytic enzymes, reactive oxygen species, nitric oxide and cytokines e.g.tumor necrosis factor (TNF), interleukin-1 (Il-1) and Il-6.Insulin-dependent diabetes mellitus may belong to this category of diseases.(13, 26)

Diagnosis of autoimmune diseases:
As there is a large number of autoantigens activating the own immune system resulting in the formation of autoantibodies by the nontolerant self-reacting B cells, diagnosis of autoimmune diseases vary from disease to disease according to the organ involved and pathogenesis.However, there are common criteria for the laboratory diagnosis of autoimmune diseases, which include high serum immunoglobulins, high serum autoantibodies (e.g.anti-nuclear, antimitochondrial, anti-smooth muscle and rheumatoid factor in RA), high serum immune complexes, high serum tissue-specific autoantibodies (e.g.anti-thyroid antibodies), high serum soluble cytokine receptor (e.g.13) Current treatment modalities for autoimmune diseases: Current treatment for autoimmune diseases is directed towards treating the 3Cs (cause, condition and complications) with limited success in some cases.Pharmacological treatment involves anti-inflammatory agents e.g.steroids (5) and non-steroidal antiinflammatory drugs to decrease the inflammatory reaction and to lower the production of inflammatory mediators upon immunological attack by the own immune system.Cytotoxic and immunosuppressive drugs may be helpful to decrease the activity of the immune cells e.g.methotrexate. (9)Cytokine inhibitors e.g.anti-TNF may lower the pathological effects exerted by the excess pathological TNF cytokines.
(30) Monoclonal antibodies are directed therapeutically to bind to inflammatory cytokines (31) e.g.infliximab binds to TNF when treating RA. (32) However, therapeutic monoclonal antibodies are so expensive and carry numerous serious side effects.(13, 34)

Al-hijamah (wet cupping therapy of prophetic medicine) clears blood from CPS
Histologically, ultrastructure of the skin (as evidenced by electron microscopic studies) is formed of three layers: epidermis, dermis and hypodermis(Fig.1A-B).Epidermis is the outermost superficial layer that contains no blood capillaries.Uppermost layer of the epidermis is a layer of non-viable cells, the keratinized epithelium layer (stratum corneum = horny cell layer) that constitutes the skin barrier (having an average thickness of 10-20 µm) whose main function is to provide the primary barrier for the percutaneous absorption or excretion of substances and water across the skin.Underlying the stratum corneum is the viable epidermis (50-100 µm thick), that is responsible for the regeneration of the stratum corneum. (35) The dermis (1-2 mm thick) is the second cell layer of the skin that is directly adjacent to the epidermis and provides the mechanical support for the skin.The fenestrated skin capillaries lie at the dermo-epidermal junction. (35)Those superficial fenestrated capillary networks (36)(37)(38) are suitable for the function of pressure-dependent filtration upon application of negative suction pressure as that done during Al-hijamah.
Practically, when performing Al-hijamah, skin scarifications (small superficial incisions, shartatmihjam in Arabic) done during Alhijamah should be so superficial (about 0.1 mm in depth) just to open the skin barrier and reach the superficial fenestrated dermal capillaries.No need to scarify the skin deeply during Al-hijamah in order not to damage the fenestrated dermal capillaries (causing loss of capillary fenestrations and filtration function) or cause unnecessary enormous bleeding. (39) The term wet cupping therapy (WCT) includes both Chinese (traditional) WCT and Al-hijamah (WCT of prophetic medicine). Traditional WCT has two main steps: scarification of the intact skin (not preceded by cupping) and suction using sucking cups applied to the skin surface i.e. double S technique.Al-hijamah has three main steps: 1 st suction step using sucking cups applied to the intact skin (not preceded by a cupping step) to create skin upliftings, scarification of the skin uplifting (shartatmihjam) and a 2nd suction step i.e. triple S technique.This is immediately followed by pressure-dependent excretion of the CPS through the shartatmihjam according to the evidence-based Taibah mechanism (Taibah theory) (11)(12) suggested recently by Salah M. El-Sayed.Taibah mechanism states that Alhijamah is a minor surgical excretory therapeutic procedure than can clear both the interstitial spaces and blood partially from noxious substances causing the disease etiology or resulting during disease pathogenesis.This occurs through making use of the skin histological structure where the fenestrated skin capillaries may act as filters upon application of suction pressure produced inside the sucking cups during Al-hijamah.(11)(12) This may facilitate regaining physiological homeostasis and recovery to variable extents depending on the degree of clearance of noxious substances, proper practice of Alhijamah at relevant anatomical sites and on the other therapeutic benefits that can be gained during disease treatment using Al-hijamah. (12)cientific principles of Al-hijamah are similar to the principle of abscess evacuation where compression pressure on the abscess walls from outside evacuates pus (noxious substances in Al-hijamah) through the created abscess openings (represented by skin scarifications in Al-hijamah). (12)Medical bases of Al-hijamah are similar in principle to renal glomerular filtration where the pressure difference between the hydrostatic capillary pressure and Bowman's capsule (represented by the pressure difference between sucking cups and skin capillaries during Al-hijamah) helps pressure-dependent filtration of the skin blood capillaries. CPS include both substances causing the disease process and substances resulting during disease pathogenesis.
(1-4)  The first and the last steps in Al-hijamah are sterilization of skin in a totally aseptic atmosphere. Cupped blood is the bloody excretion inside sucking cups that includes excreted disease CPS (Fig. 5, 6A-C). Steps of Alhijamah include two suction steps (two pressure-dependent filtration steps); while traditional WCT includes a single suction step (a single filtration step).For that, Al-hijamah is therapeutically better than traditional WCT for the better blood clearance during Al-hijamah and for many other causes as previously reported.
(11-12, 42)  -Sucking cups should be applied immediately after scarifying the skin upliftings.Shartatmihjam is induced here in the dorsal surface of the kahel region (skin over the 7 th cervical vertebra).

Figure 4B.(Skin scarification = shartatmihjam in Arabic). (Skin scarifications of Al-hijamah = shartatmihjam in Arabic). Shartatmihjam is done here at local anatomical areas at/ or very near to the site of pathology for the aim of better local tissue clearnce.
-Skin scarifications should be confined to skin upliftings, superficial (0.1-0.2 mm in depth), short (1-2 mm in length), multiple and evenly distributed.Cups should be applied immediately after scarifying skin upliftings.
-Shartatmihjam is induced here in the dorsal surface of the foot region.Indeed, Al-hijamah is more comprehensive than traditional WCT and includes all steps and therapeutic benefits included in traditional WCT and treats all disease conditions treated by traditional WCT.Opposite is not true as traditional WCT is a partial form of Al-hijamah.We previously reported so many therapeutic benefits related to Al-hijamah and explained to what extent that is beneficial in treating so many different disease conditions. (42)This can be explained by knowing that Al-hijamah induces non-specific general blood clearance from noxious substances, immunological enhancement, pharmacological potentiation, analgesic effects, physiotherapy benefits, hemostatic benefits, hematological benefits, hemodynamic benefits, nutritional benefits and others as we previously discussed. (42)All those therapeutic benefits help the restoration of homeostasis and recovery from the disease condition.To our knowledge, there are no reported serious side effects, limitations or absolute contraindications related to the proper practice of Al-hijamah.Therapeutic indications of Al-hijamah were reported previously. (42)In other reports, non-specific blood clearance occurring during Al-hijamah was reported to clear venous blood from ferritin (ng/ml) by about 22%, from LDL-Cholesterol (mg/dl) by about 23%, from triglycerides (mg/dl) by about 27%, from cholesterol (mg/dl) by about 13.7% and from serum uric acid (mg/dl) by about 17%.
(43) Blood samples were taken before Alhijamah and ten days after it, (43) which measured the excretory and blood clearance benefits of Al-hijamah.Recently, we suggested Al-hijamah as a novel promising treatment modality for iron overload conditions e.g.thalassemia. (44)Based on that, Al-hijamah can be regarded as an artificial excretory procedure that opens the skin barrier and enhances the natural excretory functions of the skin (11)(12) as evidenced by the report that WCT enhanced the patients' natural immunity via increasing the number of natural killer (NK) cells and inducing leukocytosis. (45)The pressure-dependent filtration and excretion through Al-hijamah is similar in scientific principle to that occurring in the renal glomeruli and to that occurring during the pressuredependent abscess evacuation where excretion of noxious CPS causes systemic blood clearance and restores physiological homeostasis according to the evidence-based Taibah mechanism. (12)essure-dependent excretion in Alhijamah versus the renal glomeruli (table 2) Largemolecules e.g.β-lipoprotein (Low density lipoproteins, LDL) cannot be filtered through the renal glomeruli, as their molecular weight (1,300,000) is too large to be filtered.Metabolism of LDL and other lipoproteins occur naturally inside the human body.However, excess pathological increase in LDLcholesterol is a risk factor for the development of atherosclerosis and coronary heart diseases. (43)LDL binds to LDL receptor in the hepatocyte surface where an endocytosis process occurs resulting in the formation of endosomes.Then, the endosome fuses with a lysosome carrying hydrolytic lysosomal enzymes that hydrolyze the components of LDL-cholesterol into cholesterol esters, LDL proteins, and other lipids. (46)LDL was reported to be cleared percutaneously during Alhijamah, (43)   which confers therapeutic excretory functions to Al-hijamah that cannot be attained by physiological urinary excretion.However, other large molecules e.g.(49) Recently, serum IgE and IL-2 levels significantly decreased in patients having skin dermatoses after Alhijamah, which confirms their excretion in the cupped blood. (50)Methodology described in this study was the triple S technique (Alhijamah) not traditional WCT although the authors mistakenly described it as Chinese WCT. (50)n other words, WCT opens the skin barrier and enhances the natural excretory role of the skin.This may help in excreting abnormally increased gamma-globulins (e.g.rheumatoid factor), which was reported to be decreased significantly in serum of RA patients following Al-hijamah.
Interestingly, large-sized macromolecules e.g.β-lipoproteins were reported to pass through the fenestrated pores of the skin capillaries out to the skin interstitial fluids, (47)(48)(49) which may facilitate their excretion through Al-hijamah as evidenced by previous studies.
(11-12, 47-49) Excretion through the renal glomeruli is limited to hydrophilic substances while excretion through Al-hijamah includes both hydrophilic and hydrophobic substances e.g.cholesterol and triglycerides. (43)The excretory pressure gradient utilized during Al-hijamah (-150 -430 mm Hg) is much higher than the net pressure gradient utilized for filtration at the renal glomeruli (10 mm Hg).Al-hijamah exerts a final excretion into the cupped blood while the glomerular filtrate has to undergo tubular reabsorption and secretion processes before final excretion. In reactive hyperemia, vascular compression causes a decrease in the blood supply to the skin for few minutes resulting in accumulation of vasodilator metabolites.As soon as vascular compression is removed, blood flow to the skin dramatically increases, which is called hyperemia. (52)This brings more blood to the skin circulation and enhances the clearance of blood from CPS.Moreover, WCT was reported to increase filtration at both capillary ends to clear blood from CPS to restore physiology and homeostasis (11)(12) (Fig. 4-7).

Al-hijamah as a reported promising treatment for rheumatoid arthritis
In Arabic countries, the scientific terms WCT, blood cupping therapy and bloodletting cupping therapy refer to the triple S technique (Al-hijamah) not the double S technique (traditional WCT) as Al-hijamah is an inherited modality of treatment since the era of prophetic medicine in the Arabic medical literature.Recently, bloodletting cupping therapy was reported to successfully treat autoimmune diseases e.g.RA where the pain of RA was maximally reduced.
(45) Interestingly, CPS of RA e.g.rheumatoid factor (RF) and soluble interleukin-2 receptors (SIL-2R) were reduced significantly in patients' venous blood after Alhijamah, which gave the conclusion that those CPS were excreted in the cupped blood during the pressure-mediated filtration in WCT (Alhijamah).
Interestingly, Al-hijamah was reported to increase the number of NK cells.(1-4, 13) Recently, traditional WCT (partial form of Al-hijamah) was reported to clear blood from pain-mediating substances e.g.substance P, which may explain partially the analgesic and antinociceptive effects of Alhijamah.
(54) Excretion of RF, SIL-2R and other CPS of RA through Al-hijamah (45) constitutes a nonspecific serum clearance in those patients that is so beneficial and paves the way for facilitating the therapeutic benefits exerted by pharmacological treatments.When a significant serum clearance is achieved, pharmacological treatments will be directed towards a lower concentration of CPS, which will be easier to manage pharmacologically.Excretion of disease CPS may be better than treating those CPS or abolishing their pathologic effects while they are present inside the human body. (55-56)

Lessons gained from treating RA with Alhijamah
An interesting single study was done in Al-Azhar university in Cairo, Egypt (45) that evaluated the improvements in rheumatoid Figure 7. Restoration of physiology and homeostasis.This occurs after pressuredependent excretion of CPS of autoimmune diseases during Al-hijamah patients treated using a combination of Alhijamah with conventional pharmacological treatments revealed marked significant improvements in all the tested clinical parameters during the three successive months that followed Al-hijamah in a timedependent manner.Clinical improvements were progressively increasing month after month.Best improvements were recorded in the 3 rd month after performing Al-hijamah(table 3 As for the laboratory parameters measuring the natural immunity, there was a significant improvement in all the tested parameters.Physiological leukocytosis was evident where leukocytes count (x10 9 ) increased by about 44.81% in the combined treatment group versus a decrease of about 3.6% (leucopenia) in the conventional treatment group.Percentage of NK cells (NK Cell %) increased by about 33.29% in the combined treatment group versus 1.17% in the conventional treatment group. (45)Based on that, Al-hijamah enhanced the natural innate immunity and suppressed the pathological immunity (autoantibodies, inflammatory cytokines production and immune pathologyrelated inflammatory reactions).
As for the pharmacological potentiation effects, they measured the percentage ratio of therapeutic effects of a combination of Alhijamah with conventional treatment (e.g. for RA) versus the conventional treatment group (i.e. % improvement after combined treatment / % improvement after conventional treatment).All the measured parameters of pharmacological potentiation were significant.Using the values in table 3, calculated therapeutic beneficial effects improved after combined treatment (versus conventional treatment only) by 2.95 folds for VAS, by 2.235 folds for TJC, by 4.333 folds for SJC, by 8.25 folds for DAS, by 18.04 folds for SIL-2R, by 7.39 folds for ESR, 6.95 folds for CRP, by 2.87 folds for RF, by 12.44 folds for percentage increase in leucocytes (leukocytosis) and by 28.45 folds for percentage increase in NK cells. (45)This confirms the evidence-based Taibah mechanism (Taibah theory for scientific mechanisms and rationale of Al-hijamah) (11)(12) where Al-hijamah exerts synergistic effects with pharmacological treatments when treating RA. (45) As Al-hijamah is a mechanical (not a pharmacological) line of treatment, no chemical interaction or pharmacological antagonism will occur when combining Alhijamah with pharmacological treatments.
However, for further future research studies, it will be better to specify a separate study group to investigate the pure therapeutic effect of Al-hijamah only, which may help in quantitating to what extent is the participation of Al-hijamah as a sole treatment in relieving patients with RA.It is important to mention some technical details during reporting the therapeutic results of Al-hijamah e.g. the best anatomical sites for putting sucking cups for treating RA and the possible therapeutic rationale beyond selecting the joint anatomical sites and the remote anatomical sites.Interestingly, we recently reported the therapeutic rationale beyond selecting local and general anatomical sites for treating many diseases including RA. (57) Briefly, as we had learnt from prophetic medicine, putting sucking cups at the affected joint sites clears the interstitial fluids of the selected areas from disease CPS while putting sucking cups at the remote anatomical sites from the site of pathology e.g. in the back of the trunk and the back of the neck clears better the serum from CPS. (57) Cumulative clearance of both serum and interstitial fluids (through excretion of noxious substances partially or totally) may help improving disease pathophysiology, restore physiological homeostasis (Fig. 7), and terminate or ameliorate disease pathogenesis which may be reflected positively upon improving the clinical outcome.Putting sucking cups at sites of pathology (e.g.inflammation) helps to clear those sites from substances causing the pathology (e.g.inflammatory mediators).
Moreover, the authors were not successful when they did not estimate the laboratory parameters in the first few hours after Alhijamah to report on the pure excretory benefit that occurred due to Al-hijamah-induced blood and interstitial fluid clearance.
The improvement that occurred in the clinical condition of RA patients was secondary to the subsidence of the autoimmunity and inflammatory reactions secondary to the decrease in serum parameters of the noxious substances and the physiological increases in serum parameters of WBCs and NK cells.The improvement that was reached in the 3 rd month after Al-hijamah is due to the combinatory effect of CPS excretion (immediate therapeutic benefit after Al-hijamah), immunity enhancement (gradually increasing therapeutic benefit) and subsidence of pathology (secondary therapeutic benefit to blood clearance and immunomodulation).

Therapeutic importance of clearing ferritin in autoimmune diseases using Al-hijamah
Ferritin is the circulating iron storage protein that is regarded also as an acute phase reactant marker exhibiting high levels in different inflammatory conditions.Hyperferritinemia was reported in SLE patients, diabetic patients, multiple sclerosis patients, and RA patients.Hyperferritinemia is a marker of disease activity in SLE patients. (58)Compared to subjects with normal ferritin levels, a significantly greater proportion of patients with hyperferritinemia had thrombocytopenia, lupus anticoagulant and anti-cardiolipin antibodies, which may suggest that hyperferritinemia may be an early marker in secondary antiphospholipid syndrome in SLE patients. (59)levation of serum ferritin was documented in patients with juvenile RA and was helpful in monitoring the response to therapy.
(60) Ferritin may have a role in the pathogenesis of autoimmune diseases e.g. the antiphospholipid syndrome.Hyperferritinemia was reported to be correlated with the antiphospholipid syndrome, its catastrophic variant and the presence of anti-CMV antibodies among those patients. (61)oreover, hyperferritinemia (≥1,250 µg/L) was reported to rule out some autoimmune diseases and hematologic diseases (62) where increased serum ferritin and reduced activity of iron-regulatory proteins were reported to indicate monocyte iron accumulation, which may be important for the pathophysiology of anemia of chronic diseases in humans.
Furthermore, hyperferritinemia (≥2,500 µg/L) was reported to be associated with the relapsing-progressive type of multiple sclerosis, (64) adult-onset Still's disease, (65) primary and secondary hemophagocyticlymphohistiocytosis.(66)(67) Interestingly, low serum ferritin was reported to be associated with a good response to therapy in patients with autoimmune diseaseassociated hemophagocytic syndrome (66-67) that usually presents with hyperferritinemia (> 500 µg/L), high fever, hepatosplenomegaly, lymphadenopathy, central nervous system involvement and disseminated intravascular coagulation.(68) Based on that, significant clearance of serum ferritin in patients having autoimmune diseases using Al-hijamah is so beneficial in correcting the pathogenesis in such patients and in restoring physiological homeostasis (Fig. 7).Al-hijamah versus phlebotomy and plasmapheresisTherapeutic benefits and improvements reported after Al-hijamah were better than those reported after phlebotomy (69-71) where Al-hijamah improved much better the arterial O 2 saturation and respiration when treating smoking in patients having chronic obstructive pulmonary diseases without causing significant blood loss.(69) Al-hijamah was reported to do better than phlebotomy in decreasing CRP dramatically and improving the ESR in patients having chronic urticaria and angioedema.
(70) Methodology described in those studies was the triple S technique (Alhijamah) not traditional WCT.Detailed differences between Al-hijamah and phlebotomy were previously reported. (44,71) toimmune diseases (including RA) exhibit a similar abnormality in blood chemistry as in RA i.e. they have high serum level of autoimmune antibodies and immune complexes (tables 3-4).
Plasmapheresis (plasma exchange transfusion) is used for treating some autoimmune diseases to clear blood plasma from autoimmune antibodies.
(72-74) Plasmapheresis aims at removing immune mediators as autoantibodies, immune complexes, and proinflammatory substances e.g.complement components and coagulation factors.
(72-74) Diseases treated by plasmapheresis include Goodpasture'sdisease (in which antiglomerular basement membrane antibodies are present), SLE, myasthenia gravis and Guillain-Barre syndrome.Plasmapheresis is an expensive, risky, sophisticated, time-consuming (1-3 hours) excretory treatment that needs a special plasmapheresis machine.Preparatory steps for plasmapheresis include assessing hematological indices and plasma volume.
Steps of plasmapheresis include separating plasma from blood cells and discarding plasma.(74) Massive sudden removal of antibodies during plasmapheresis may lead to a rebound increase in the production of autoantibodies. (74)So, plasmapheresis should be done under the umbrella of immunosuppressive therapy to decrease the possibility of rebound increase in autoantibodies (75-76) (table 5).

 Pharmacological potentiation cells below 37°C Disease
As for Al-hijamah, it may have some advantages over plasmapheresis in clearing blood from the offending CPS without the need for the sophisticated plasma exchange transfusion (therapeutic plasma exchange) (table 5).During the first step in Al-hijamah, collected interstitial fluids with CPS, filtered fluids (from blood capillaries containing CPS) and hemolyzed blood cells accumulate inside the skin upliftings (domes) induced during suction steps of Al-hijamah.No intact blood cells (RBCs, WBCs and platelets) exist in this fluid mixture.Blood cells have diameters in microns that are about 100-1000 times larger than the pores of the skin capillaries (6-100 nm in diameter) and are therefore too big to pass through the pores of the skin capillaries (11)(12) and cannot be filtered.Puncturing skin upliftings and applying second suction step excrete collected fluids beneath the skin barrier.Superficial scarifications open the skin barrier (1 st layer of epidermis) and transmit the suction pressure to the superficial fenestrated skin capillaries to make them act as filters for exerting a pressure-dependent filtration and excretion of the small sized noxious substances circulating in the fenestrated subepidermal capillaries.Superficial nature of the skin scarifications is quite important to ensure that there is no damage to the superficial skin capillaries.However, inevitable minor trauma may occur to the capillaries at some scarification points and cause the excretion to be bloody.
(42, 44, 71) Superficial skin scarifications (shartatmihjam in Arabic) represent proper practice of Al-hijamah while deep skin scarifications may injure deeper blood vessels and represent a malpractice that may cause significant bleeding.Al-hijamah is a pressure-dependent filtration procedure that is done through the fenestrated skin capillaries using suction pressure created inside suction cups.Reported sucking pressure (from -200 to -560 hecta Pascal, equivalent to -150 to -420 mmHg) was reported to be created inside the sucking cups during WCT. (78)This suction pressure (filtration force) is transmitted (through skin scarifications = shartatmihjam induced during WCT) to around the skin capillaries to be added to the capillary hydrostatic pressure (-33 mmHg at the arterial end of capillaries and -13 mmHg at the venous ends of capillaries) (11-12, 78) that drives fluids to the outside of the fenestrated skin capillaries against the capillary osmotic pressure (+ 20 mmHg) (11)(12)78) that drives fluids to the inside of the skin capillaries.
By mathematical calculation of pressure differences, a pressure gradient and a traction force across the skin and capillaries are created leading to increased filtration at the arterial end of capillaries at net pressure of -163 to -433 mmHg and at the venous end of capillaries at net pressure of -143 to -413 mmHg (11-12, 77-78) resulting in clearance of blood from fluids containing CPS of autoimmune diseases (autoantibodies, immune complexes and inflammatory cytokines) (tables 2, 5).
Moreover, pharmacological potentiation induced by WCT to current treatment modalities in treating autoimmune diseases was proven.(42, 44-45) This can be explained on the basis that WCT excretes CPS and facilitates the therapeutic roles exerted by the conventional pharmacological therapeutics.Interestingly, Al-hijamah is a highly recommended treatment in prophetic medicine where Prophet Muhammad peace be upon him said:" Cure is in three: in sharatamihjam, gulp of honey and cauterization.I do not recommend my nation to cauterize". (79)

Al-hijamah for treating other autoimmune diseases
Compared with RA, other autoimmune diseases may have a similar pathogenesis and blood chemistry to some extent in which CPS may include autoantibodies, immune complexes, inflammatory mediators, cytokines, products of autoreactive immune cells and others (tables 3-5).Al-hijamah-induced nonspecific blood clearance from disease CPS, activation of natural immunity, pharmacological potentiation, analgesic effect and other therapeutic benefits (11-12, 42) may be promising in treating such diseases.Based on that, Alhijamah may be a promising treatment for autoimmune diseases through its serum and local interstitial fluid clearance effect from CPS. Autoimmune antibodies that are present in serum of autoimmune patients were reported to be excreted outside the human body through Al-hijamah, (45) which may be beneficial in inhibiting the progression steps of pathogenesis of autoimmune diseases and in potentiating the therapeutic effects of current pharmacological treatments.
In conclusion, Al-hijamah may be promising in treating different autoimmune diseases (Table 6) as a sole treatment or adjuvant treatment to current treatment modalities.Alhijamah may be superior to plasmapheresis (plasma exchange transfusion (72-73, 81-83) in many points when treating autoimmune diseases (Tables 4-6).

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Termed negative autoselection Involves deletion of autoreactive B-cells --Occurs when immature B-cell receptors mistakenly bind to self-antigens and become autoreactive.B. Peripheral tolerance Occurs outside the thymus and bone marrow -Autoreactive cells become inactivated through several mechanisms as: --Absence of appropriate MHC molecules -Lack of co-stimulatory molecules Lack of T-cell help for B-cells activation --Active suppression of autoreactive cells (mediated by T-cells).

Figure
Figure 2.Causative pathological substances (CPS) of autoimmune diseasesare present in serum and interstitial fluids.CPS can be filtered through capillary pores then excreted out through the pressuredependent effect of Alhijamah.

Figure 3A .
Figure 3A.Skin uplifting (dome) created after putting sucking cup in the kahel region

Figure 3C Figure
Figure 3C

Figure
Figure 4. Second step in Alhijamah is shartatmihjam.Openings of the skin barrier through skin scarifications (shartatmihjam in Arabic) allow the excretion of the collected fluids containing CPS mixed with some blood due to scarification trauma.A. Shartatmihjam was created in the Kahel region.B.Shartatmihjam was created on the dorsuma of the foot region.C. detailed pressure-dependent excretion occurring through shartatmihjam.

Figure 5 .
Figure 5. Third step in Al-hijamah is 2nd suction using sucking cups.Excreted cupped blood carries the filtrate mixed with some old hemolyzed and fragmented blood cells.A. Cupped blood excreted at Kahel and Akhdayin regions.B. Cupped blood excreted at local foot region.C. Pressuredependent excretion of a serous plasma-like fluid.

Figure 6 .
Figure 6.Third step in Al-hijamah is 2nd suction using sucking cups.Excreted cupped blood carries the filtrate mixed with some old hemolyzed and fragmented blood cells.A. Cupped blood excreted at Kahel and Akhdayin regions.B. Cupped blood excreted at local foot region.C. Pressure-dependent excretion of a serous plasma-like fluid.
a subset of effector lymphocytes that, in contrast to T cells, do not require prior sensitization with antigen for their immunological function.The lytic functions of NK cells are regulated by a set of inhibitory receptors (killer inhibitory receptors) recognizing MHC class I determinants on target cells.

of Al-hijamah
Better clearance of blood and interstitial fluids in healthy subjectsRenal patients benefit from Alhijamah in improving the defective clearance functions and relieving side effects of hemodialysis.Other namesCupping therapy of prophetic medicine, triple S technique Urine formation and micturition

Table 4 . Possible therapeutic role of Al-hijamah in treating different autoimmune diseases N
.B. Autoimmune diseases have common criteria that are presence of autoantibodies and inflammatory mediators