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									                     JOURNAL OF CLINICAL RHEUMATOLOGY
                                                                                                                 REVIEW ARTICLE
                        & MUSCULOSKELETAL MEDICINE



Psoriatic Disease: A Systemic Pathology, Structured by
Psoriasis, Psoriatic Arthritis and Comorbidities
J. A. O’Daly
Affiliation: Department of Research & development, Astralis Ltd, 1076 Stuyvesant Ave. Irvington, NJ, USA




                                                                A B S T R A C T

  While injecting volunteers in Venezuela with a vaccine for prevention of leishmaniasis, we observed 100% clinical remission of a psoriatic




                                                                                              C
lesion in one subject. A single center study evaluated the safety and efficacy of multiple 500 mg doses of AS100 on psoriatic arthritis (PsA).
Approximately, 2599 subjects (83%) experienced at least one adverse event, injection site related and including: pain 43%, nodule formation
23%, heat 21%, and erythema 14%. When baseline Psoriasis Area and Severity Index (PASI) values in the group with PsA (n 0508) were




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compared with post-treatment values, clinical remissions were: PASI 100 in 275 (54.1%), PASI 75 in 117 (23%), PASI 50 in 73 (14.4%), and
PASI 10 in 43 (8.5%) of subjects, respectively. The number of AS100 doses required to induce 100% remission was 9.994.8. Higher
percentage frequency in PsA than psoriasis patients was found in hypertension, vascular diseases, intestinal diseases, infections, gastritis,
cardiac arrhythmia, gallstones in gallbladder, osteoporosis, hyperuricemia, and epilepsy. Up to 7Á8 comorbidities were found in both
psoriasis and PsA patients together in the same subject: thus, psoriasis is a systemic disease, induced by cytokines in all body organs,
being expressed in each tissue according to genetic and environmental factors due to shared inflammatory pathways. Development of
                                                                                 al,
psoriasis and PsA is centered in the blood vessels’ behavior. Both diseases start by proliferation of blood vessels after up-regulation of
vascular endothelial growth factor, transforming growth factor b, and other angiogenic factors. Clinical remission in psoriatic lesions also
starts by decreased proliferation of blood vessels, after treatment with leishmania antigens.
                                                                  dic
  Keywords: psoriasis systemic disease, psoriasis comorbidities, psoriatic arthritis, psoriasis vascular disease

  Correspondence: J. A. O’Daly, Department of Research & development, Astralis Ltd, 1076 Stuyvesant Ave. Irvington, NJ 07111, USA.
Tel: 1-973-224-5723; e-mail: joseodaly@aol.com
                                                     Me


INTRODUCTION                                                                     from 1982 to 1992 in the same community revealed an
                                                                                 incidence rate of 6.59% per 100,000 US population.4
  Louis Aliberti, in 1818, first noted the relationship
between psoriasis and arthritis. Pierre Bazin then described                      PsA is characterized by stiffness, pain, swelling, and tender-
‘‘Psoriasis Arthritique’’ in 1860, followed by Charles Bourdil-                  ness of the joints as well as adjacent tendons and ligaments
lon in 1888 with ‘‘Psoriasis et Arthropathies.’’ Jeghers and                     with a penetrance from 6% to 42% in the population with
                                          ˜ol
Robinson in 1937 and Vilanova and Pin in 1951 described                          psoriasis. A clinical trial demonstrated that 84% of patients
                                        as




psoriatic arthritis (PsA) as a unique entity. PsA was recog-                     with PsA had only skin disease for an average of 12 years
nized after Verna Wright published a comparative study of                        before the development of PsA.5
rheumatoid arthritis (RA), psoriasis, and arthritis associated                     The psoriatic disease is a multifocal and chronic systemic
with psoriasis in 1956 and 1959. The American College                            inflammation in which genes and environment play a role.
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of Rheumatology recognized PsA as a distinct entity in 1964.1                    Erosive and deforming arthritis occurs in 40%Á60% of
                                                                                 patients with PsA. Psoriasis has not been interpreted in
  Prevalence of PsA varies in several studies (5%Á40%).
                                                                                 the past as a systemic disease; thus, comorbidities have
A large study conducted in the UK, Italy, France, Spain,
                                                                                 not been well evaluated by the dermatologist.6
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and Germany in 2006 found 8.1% prevalence of PsA in
patients with psoriasis. Survival analysis indicated that the                      T-helper cell type 1 (Th1) lymphocytes secreting cytokines,
incidence of PsA among plaque psoriasis patients remained                        including interleukin (IL)-17, IL-2, IL-6, IL-10, IL-1b, inter-
constant at 74 per 100 person/years, whereas the prevalence                      feron g (IFN g), and tumor necrosis factor a (TNFa)
increased with time since diagnosis of psoriasis, reaching                       among many cytokines, are found in psoriatic synovium
20.5% after 30 years.2                                                           and skin plaques and are provoking not only proliferation and
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                                                                                 abnormal differentiation of keratinocytes and synoviocytes
  A population based study in Minnesota USA reported the                         but also a systemic reaction cause of many inflammatory
annual incidence of PsA per 100,000 to be 7.2. The incidence                     diseases in the same patient, where the cytokine TNFa
increased from 3.6 between 1970 and 1979 to 9.8 between                          plays the most relevant role.7 Such comorbidities include
1990 and 2000, providing the first evidence that the incidence                   PsA, metabolic syndrome (MS), palm-plantar pustulosis,
of psoriasis increased during recent decades.3 A second study                    inflammatory bowel disease, cardiovascular disease (CVD),



www.slm-rheumatology.com                                                     1                                   JCRMM 2011; 2:(2). Month 2011
The Journal of Clinical Rheumatology and Musculoskeletal Medicine



hypertension (HTA), myocardial infarct (MI), autoimmune               vessels noted in psoriatic skin and synovium, has been
diseases, psychiatric illness, diabetes mellitus (DM), liver          found in early psoriasis and PsA.19Á21
disease, smoking, cancer at specific sites, obesity, chronic            Concentration of serum VEGF and VEGF receptors (sVEGF-
obstructive pulmonary disease, sleep apnea, alcohol abuse,            R1, -R2) demonstrated significant correlation with psoriasis
and depression.8                                                      area and severity index (PASI). Levels of serum VEGF and
  The Classification of Psoriatic Arthritis (CASPAR) study            sVEGF R1 were the highest in patients with PASI !20.22
group was established as classification criteria for PsA.             In vitro culture studies revealed that VEGF and other
The CASPAR criteria comprised: (1) Evidence of psoriasis              cytokines in the skin are secreted predominantly by kerati-
as judged by a rheumatologist or dermatologist, personal              nocytes and its concentration is enhanced in both involved
and family history from patient, (2) psoriatic nail dystrophy,        and uninvolved skin of patients with psoriasis suggesting
including onycholysis, pitting, and hyperkeratosis, (3) a             that the epidermis is capable of inducing vascular prolife-
negative test for rheumatoid factor (RF), (4) dactylitis,             ration.23,24 VEGF receptors are also overexpressed in lesional
current swelling of an entire digit, or history of dactylitis,        psoriatic epidermal keratinocytes, are stimulated by VEGF
and (5) radiological evidence of juxta-articular new bone             itself, and are capable of binding VEGF, preventing proan-




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formation as ill-defined ossification near joint margins on           giogenic signal transduction that can be a clinically relevant
hand or foot. Using the CASPAR criteria, the combination              strategy for the inhibition of angiogenesis.25




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of psoriasis and inflammatory arthritis gave .96 for sensiti-           In skin and synovium of PsA, there is infiltration of
vity and .97 for specificity, respectively.9Á11                       neutrophils, positive for receptors VEGF-R1, -R2, together
  Three main clinical patterns have been identified in PsA:           with a prominent T cells infiltrate, localized in epidermis,
(1) oligoarticular (54 involved joints) or polyarticular              dermal papillae, and to the sublining stroma in the joints
(]5 involved joints), (2) peripheral disease, and (3) axial           as well as the inflamed enthesis.26 TNFa activates EC,
disease with or without associated peripheral arthritis. Distal
interphalangeal arthritis and arthritis mutilans may also
                                                                       al,
                                                                      leading to expression of adhesion molecules, including
                                                                      vascular cell adhesion molecule-1 (VCAM1), intercellular
                                                                      adhesion molecule-1 (ICAM1), and E-selectin, all molecules
occur. Asymmetric oligoarthritis is the most frequent pattern
at onset. Axial disease has been estimated between 5% and             responsible for lymphocyte migration to sites of inflamma-
                                                                      tion.27 TNFa also plays a role in cartilage degradation via
                                                          dic
36% of patients, characterized by predilection for the
cervical spine. Recurrent episodes of enthesitis and dactylitis       increased production of matrix metalloproteinases that are
represent a hallmark of PsA. In 20% of cases, distal extre-           thought to mediate cartilage erosion.28,29
mity swelling with pitting edema of the hands or feet is                A predominance of CD8' T lymphocytes has been noted in
observed. Unilateral acute iridocyclitis, usually recurrent in        both the synovial fluid and entheses of patients with PsA.30
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alternate fashion, is the most frequent extra-articular mani-         PsA is associated with clonally expanded CD8' T cells
festation (2%Á25%), and accelerated atherosclerosis is the            independently from the participation of CD4' T cells.31
prominent comorbidity.12                                              PsA explants in vitro released elevated levels of interleukin
  Development of blood vessels from in situ-differentiating           IL-1b, IL-2, IL-10, IFNg, and TNFa but not IL-4 or IL-5.
endothelial cells (EC) is called vasculogenesis; whereas,             A similar pattern of gene expression was detected in
sprouting of new blood vessels from the preexisting ones              whole synovial tissue. Levels of IFNg, IL1b, and IL-10
                                    as




is termed angiogenesis or neovascularization. Angiogenesis            were higher in psoriatic synovium than psoriatic dermal
is essential for tissue repair, fetal development, and                plaques.32
female reproductive cycle.13,14 One of the most specific and            The chronic inflammatory state of PsA and psoriasis
critical regulators of angiogenesis is vascular endothelial           contributes to the accelerated atherosclerosis. Aortic pulse
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growth factor (VEGF) that regulates endothelial proliferation,        wave velocity was reduced after treatment with TNFa anta-
permeability, and cell survival.15,16 Microvascular alterations       gonists in parallel to decrease in C-reactive protein (CRP)
are essential for the development and persistence of the              and PASI values.33 The theory of passive lipid artery accumula-
psoriatic lesions as they provide cellular and tissue nutrition       tion leading to plaque formation has changed because
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to hyperplastic keratinocytes and promote inflammatory                it has been demonstrated that systemic inflammation, invol-
cell migration. Dilated and tortuous blood vessels within             ving inflammatory activity in the vascular wall, is fundamental
dermal papillae represent one of the earliest detectable              in the pathogenesis of atherosclerosis. Many inflammatory
histological changes for all stages of lesional development           cells and cytokines, including TNFa, play an active role in
in psoriasis.17 Dysregulation of angiogenesis and lymphan-            atherosclerosis, similar to their role on PsA and psoriasis.34
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giogenesis participates in psoriasis pathogenesis. Expansion          The mean serum VEGF concentration was higher in patients
of lymphatic vessels occurs after blood vascular development          with active PsA (394.4 pg/ml), in contrast to lower values
in psoriasis.18 A balance between proangiogenic and anti-             in inactive PsA (200.4 pg/ml) and controls (214.3 pg/ml).35
angiogenic growth factors and cytokines tightly controls              PsA patients (35%) had a higher prevalence of sub-
angiogenesis. Up-regulation of VEGF and transforming                  clinical atherosclerosis, with significantly increased sugar,
growth factor b (TGFb), providing the distinctive tortuous            total triglyceride levels, white cell count, and patients’ global


JCRMM 2011; 2:(2). Month 2011                                     2                                        www.slm-rheumatology.com
                                                                                                                  Psoriatic disease



assessment score compared with those without subclinical              patterns (PAMPs), and also enzymes such as cyclooxygenase-
atherosclerosis.36                                                    2 (COX2) and inducible nitric oxide synthase (iNOS).46,47
  Diabetes mellitus and HTA were found in a higher                      Animal models of atherosclerosis have shown a very early
proportion in PsA patients, who had a significantly lower             role for heat shock protein 60 (HsP60) in the development
prevalence of low HDL cholesterol than controls, whereas              of the disease. Enhanced levels of circulating HsP60 are
the prevalence of hypercholesterolemia and hypertriglycer-            associated with early atherosclerosis in clinically normal
idaemia was similar in both PsA and control groups.                   subjects. More than 95% sequence homology exists on
The total cholesterol and low-density lipoproteins (LDL)              both the DNA and protein levels, basis for extensive
cholesterol levels were significantly lower; in PsA patients.37       immunological cross reactions between pathogens including
These facts underline the role of the vessel wall inflam-             parasites and autologous HsP60. The first cell types
mation in atherosclerosis.                                            found in the arterial intima at atherosclerotic lesions are
                                                                      lymphoid cells followed by macrophages and SMC. Within
  Cardiovascular disease is more prevalent in those with
                                                                      the T cell population in these early lesions, activated
moderate to severe psoriasis than in the general population.
                                                                      CD4' HLA-DR'CD25' T cells prevail over CD8' cells
A large cohort study revealed a greater than normal inci-




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                                                                      T cells.41
dence of MI in patients with mild and severe psoriasis.
Patients with psoriasis are at high risk of developing DM,              The MS is a constellation of interrelated risk factors of
                                                                      metabolic origin that appear to directly promote the devel-




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HTA, obesity, hyperlipidemia, MI, angina, atherosclerosis,
peripheral vascular disease and stroke, reinforcing a connec-         opment of atherosclerotic CVD and type II DM. MS is
tion between psoriasis, the systemic inflammation, and heart          defined as a state of chronic systemic inflammation and
disease.38 A follow-up study demonstrated similar results             the presence of abdominal obesity, increased insulin resis-
in psoriatic patients: HTA (60.1%), obesity (6.3%), DM                tance, elevated fasting glucose level, impaired glucose
(27.3%), dyslipidemia, (31.6%), smoking (9.9%), and mor-              regulation, decreased high-density lipoprotein, hypertrigly-
                                                                      al,
tality (19.6%). Psoriasis is an independent risk factor for           ceridemia, and HTA.48,49 Increased incidence of MS and
mortality; with a higher percentage of deaths among                   CVD has been found in PsA compared with the general
patients with psoriasis (19.6%) than among patients with-             population. Studies report that plasma acute phase proteins
out psoriasis (9.9%).39                                               were significantly elevated in patients with psoriasis com-
                                                       dic
                                                                      pared with healthy controls.37,42
  The increased CVD depends on the inflammatory nature
of psoriasis that plays a significant role in atherogenesis            Cohort analyses followed up from 1978 to 2004 revealed
and in the formation of early fatty streaks. The immune               a malignancy in PsA at an average age of 62.4 years.
response in atherosclerosis is modulated by two anti-                 The most frequent were breast (20.6%), lung (13.2%), and
                                                                      prostate (8.8%) cancer. However, the incidence of malig-
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inflammatory cytokines IL-10 and TGFb, both play a critical
role. Proinflammatory cytokines implicated in the generation          nancy did not differ from that in the general population.50
of atherosclerotic plaques are mainly produced by macro-
phages that also activate smooth muscle cells (SMC) and
EC similar to cytokines described in psoriasis and PsA.40             MATERIALS AND METHODS
  The lipid-laden foam cells of the fatty streak comprises            Safety Criteria for the Treatment of Psoriasis and
                                 as




an area of intimal thickening composed of macrophages                 Psoriatic Arthritis
distended by lipid droplets (foam cells), T lymphocytes, and            In all trial subjects, safety was evaluated by assessing
SMC. Plaques develop after accumulation of LDL in the                 vital signs (including heart rate and blood pressure), injec-
subendothelial space, followed by the diapedesis of leuko-            tion site reactions, and physical examinations. In a selected
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cytes, formation of foam cells, and production of connective          group of subjects, safety was further assessed by clinical
tissue.41 Psoriasis is the most common Th1 immunological              laboratory tests (comprehensive hematology and metabolic
disease. Evidence has linked Th1 diseases to MI. A cohort             profile).
was followed up for a mean of 5.4 years. There were
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2.0% MI within the control population and 1.8% and                    Efficacy Criteria Before and After Treatment
2.9% MI within the mild and severe psoriasis groups,
                                                                        Efficacy of AS100 vaccines was assessed by performing
respectively. The incidences for MI per 1000 person-years
                                                                      skin examinations and recording PASI parameters at each
for control patients, patients with mild and severe psoriasis
                                                                      visit as published.51Á54 PASI reduction was calculated as
were 3.58, 4.04, and 5.13, respectively.42Á44
                                                                      follows: [(PASI at base line)*(PASI at each visit)/PASI at
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  T lymphocytes (20%) are found surrounding the plaque                baseline] )100. The primary efficacy parameters were the
and in the fibrous cap, pointing to a role of immunity                percentage reduction in PASI score at each visit and the
in atherosclerosis.45 The NF-kB pathway is one of                     comparative proportions of subjects with 100%, 75%, and
the main signaling pathways activated in response to proin-           50% PASI improvement in each treatment group. For
flammatory cytokines, including TNFa, IL-1, and IL-18, as             analysis of LS data before treatment, PASI groups I, II,
well as following activation of the Toll-like receptors (TLR)         and III were analyzed in patients with 1Á34 years of evolu-
by the pattern recognition of pathogen-associated molecular           tion with psoriasis. PASI score changes after each dose


www.slm-rheumatology.com                                          3                                  JCRMM 2011; 2:(2). Month 2011
The Journal of Clinical Rheumatology and Musculoskeletal Medicine



of the active products were classified as follows: B10%                          an experienced dermatologist, checked by a rheumatologist
PASI reduction (PASI between 1 and 9); ]10% PASI reduc-                          in 15% of cases.52 Clinical examination of patients was
tion (PASI between 10 and 49); ]50% PASI reduction                               performed at the clinical site, and comorbidities were
(PASI between 50 and 74); ]75% PASI reduction (PASI                              recorded at the first visit as in Tables 1 and 2.
between 75 and 89): and 100% PASI reduction (PASI
between 90% and 100%) as previously published51Á54 The                           Inclusion and Exclusion Criteria
total number of subjects with Psoriasis was 3132 volunteers.                       The AS100 trial, main criteria for trial inclusion and
From that group, 508 subjects (16.22%) had PsA that                              exclusion were one and the same as previously published
meet the CASPAR criteria9Á11 and were chosen for the                             criteria. Briefly, the inclusion criteria were as follows. Eligible
analysis and comparison with 2624 volunteers with skin
                                                                                 subjects included males and females five years of age or
psoriasis but no arthritis. The study was conducted at one
                                                                                 older with active but clinically stable plaque psoriasis
medical center from March 1992 through May 2002 and
                                                                                 present for at least three months. Additional inclusion criteria
included all eight types of psoriasis: plaque (79%), guttate
                                                                                 were use of a medically accepted form of contraception
(10%), plaque and guttate (10%), palm/plantar (.3%), ery-
                                                                                 throughout the study and a negative pregnancy test (females




                                                                                                        C
throdermia (1.8%), inverse (.8%), plaque and arthritis
                                                                                 of child-bearing potential). The exclusion criteria consisted
(3.4%), and nail psoriasis (.3%) as published.51 The study
group had average age 40.5915.0 years old, 2894 (92.4%)                          of a positive leishmania infection status and a positive
                                                                                 intradermal reaction skin test for leishmania at screening.




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were between 26 and 65 years of age with a range of 5Á88
years old. One thousand ninety six subjects (35%) had                            Any female subject pregnant or lactating was excluded from
family histories of psoriasis. The average duration of disease                   the trial. Documented immunodeficiency, HIV status, oppor-
in all subjects was 11.5910.3 years, ranging from 2 to                           tunistic infections, or ongoing uncontrolled infections
62 years, similar in both males and females. The 508 group                       were a basis for trial exclusion. Subjects whose medication
with PsA had average age 44.9914.3 years old, range                              involved any vaccines, allergy desensitization products,
                                                                                    al,
5Á83 years, time with psoriasis 13.2912.4 years, range                           or use of topical therapy (except emollients) for psoriasis
.4Á64 years, 53% females. RFs determined in 3% of patients                       within two weeks preceding the first administration of the
(n 015) with PsA were negative, a low number, due to                             study medication were excluded from trial participation.
economic reasons. Eleven percent (53/508) had diagnosis                          The use of systemic retinoids, corticosteroids, cyclosporine
                                                                     dic
of psoriasis by skin biopsy, the rest by clinical criteria by                    A, methotrexate, phototherapy, coal tar treatments, or receipt

Table 1. Prevalence of Comorbidities in Psoriasis and Psoriatic Arthritis Patients Compared With Mortality Frequency in Venezuela
                                                                          Psoriatic Arthritis n0508             Skin Psoriasis n03132
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                                                                                        Morbidity                         Mortality
 Comorbidities as an event in any patient                                       n                   %               n                 %           %
 Hypertension                                                                   125                 24.6           719                22.9       2.24
 Vascular diseases ACV, hemangioma, varices, hemorrhoids                        56                  11              96                 3.1       2.26
 Intestinal disease, constipation, diverticulitis, colitis, polyps              56                  11              83                 2.7         .82
                                                as




 Diabetes                                                                       35                   6.9           152                 4.9       4.29
 Infections, oropharynx, cellulites, sinusitis, furunculous, TBC                27                   5.3            69                 2.2         .82
 Gastritis, ulcers                                                              32                   6.3            112                3.6       2.17
                        uc




 Allergies, rhinitis, asthma, contact dermatitis                                36                   7.1           338                10.8         .37
 Cardiac arrhythmia                                                              18                  3.5            49                 1.6       ND
 Myocardial infarct                                                                 7                1.4           109                 3.5       13.13
                      nL




 Gallstones in urinary tract                                                     10                  2              73                 2.3        1.44
 Gallstones in gallbladder                                                          8                1.6            28                  .9         .37
 Osteoporosis                                                                       9                1.8            23                  .7       ND
 Hyperuricemia                                                                      7                1.4            20                  .6       ND
 Epilepsy                                                                           8                1.6            23                  .7         .33
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 Diseases of uteri, Uterine fibromatosis, polyps                                 15                  3              99                 3.2       2.35
 Hepatic cirrhosis, fibrosis                                                        4                 .8            20                  .6        1.55
 Thyroid diseases                                                                12                  2.4            76                 2.4       ND
 Migraine                                                                           2                 .4            24                  .8       ND
 Hepatitis                                                                          1                 .2            23                  .7       ND



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                                                                                                                                   Psoriatic disease


Table 2. Presence of Three or More Comorbidities, in the Same Subject,                 protein. Protein concentration was determined by Lowry or
at the Same Time, in Patients With Skin Psoriasis or Psoriatic Arthritis
                                                                                       BCA.55,56
                                     Skin Psoriasis
    Comorbidities in the same patient                                         Na       Preparation of AS200 Purified Vaccine
                                                                              2
    Allergies, hypertension (HTA), diabetes                                              Preparation of second-generation AS200 immunogen from
    Allergies, HTA, diverticulitis, uterine fibromatosis, gallstones in       2        leishmania protein (DEAE) fractions was as follows: Indivi-
    gallbladder, appendicitis                                                          dual Leishmania species from AS100 polyvalent vaccine were
    Gastritis, colitis, oropharingitis, tonsillitis, hepatitis                1        separated by DEAE chromatography. The chromatographic
                                                                              1        separation resulted in seven protein fractions per each
    Asthma, rhinitis, hiatus hernia, esophagitis, gallstones in urinary
    tract, folliculitis in skin, strabismus, tonsillitis                               AS100 vaccine component for a total of 28 protein frac-
                                                                              1        tions (leishmania protein [DEAE] fractions). The fractions
    HTA, constipation, uterine fibromatosis and polyps, atopic dermatitis
                                                                                       were in turn used to formulate the second-generation
                                                                              1
    Allergies, HTA, gastritis, esophageal varices, liver cirrhosis                     immunogen (AS200). Each AS200 vaccine was prepared
                                                                              1        from each discrete protein fraction; hence, each Leishmania
    Allergies, arrhythmia, thyroiditis, uterine polyps, appendicitis




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    HTA, constipation, amebiasis, intestinal parasites infections, inguinal
                                                                              1        species (La, Lb, Lch, and Lv) potentially had seven AS200
    hernia, prostatic hyperplasia                                                      formulations as previously published.54 The final immunogen
                                                                              1        preparation contained 400 mg/ml of each of the antigenic




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    Asthma, capillary dysfunction, gastritis, dysmenorrhea
                                                                              1
                                                                                       fraction in PBS and Rehydragel at a concentration of
    HTA, pulmonary emphysema, IM, cancer urinary bladder                               .25 ml/mg (v/w) of protein. Protein content was determined
                                                                              1
    Allergies, arrhythmia, thyroiditis, uterine polyps, appendicitis                   by the method of Lowry or BCA.55,56
                                                                              1
    Gastritis, rhinitis, migraine, mycosis in skin, hepatitis B
                                                                              1        AS200 Trial
    HTA, constipation, gastritis, cancer thyroid                                       al,
                                                                              1          The AS200 study was a single-blind, controlled trial.
    HTA, allergies penicillin, ASA, merthiolate, diabetes
                                                                                       The AS200 trial included 53 subjects, 62% females average
    Allergies ASA, novalcina, voltaren, rhinitis, sinusitis                   1
                                                                                       40.6918.6-years-old, age range 7Á78 years of age, initial
                                                                                       PASI 26.4919.2, time with psoriasis 15.0912 years. The
                                                                          dic
                                   Psoriatic Arthritis
                                                                                       treatment subjects received four 200 mg/dose injections of
                                                                              2        AS200 (Lb) and control subjects received four 500 mg/dose
    Arthritis, HTA, intestinal disease, diarrheas, colitis
                                                                                       of AS1001.54
    Arthritis, HTA, diverticulitis, hemorrhoids, phlebitis                    2

    Arthritis, HTA, pulmonary emphysema, colitis                              1        Statistical Methods
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    Arthritis, HTA, diarrheas, cancer in cervix, arrhythmia, diabetes         1          The analysis was similar to previously published guide-
                                                                              1        lines used for AS100-1 trials.51Á54 The ANOVA assumption
    Arthritis, asthma, rhinitis, sinusitis, allergies ASA, novocain
                                                                                       of normality and homogeneity of variances was tested and,
a
    n0Number of patients with the same comorbidities                                   where appropriate, a nonparametric approach (Tukey’s test)
                                                                                       or MannÁWhitney’s test was used to compare treatment
of any investigational drug therapy within four weeks                                  groups. A last-observation-carried forward algorithm was
                                                as




preceding the administration of the study medication was                               used to replace missing observations. D’Agostino & Pearson
also a cause for exclusion. Subjects with a known hypersen-                            omnibus normality test and Wilcoxon Signed Rank Test
sitivity to gentamicin or local anesthesia, or diagnostic                              were used to compare column statistics. All calculations
agents used for tests pertaining to the trial protocol, and                            were done with GraphPad Prism software.
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a documented history of alcohol abuse were excluded
from trial participation as published.51Á54
                                                                                       RESULTS
Preparation of the Polyvalent Immunogen (AS100)
                     nL




  The first-generation polyvalent vaccine AS100 was pre-                               AS100 Trial
pared with four leishmania species: L.(L)amazonensis,                                    This study was an open label, single-center study that
L.(L)venezuelensis, L.(V)brasiliensis, and L.(L)chagasi. The final                     evaluated the safety and efficacy of multiple 500 mg doses of
polyvalent first generation immunogen preparation, AS100                               AS100 on PsA. Approximately 2599 subjects (83%) experi-
drug substance, contained 1 mg/ml or 250 mg of each                                    enced at least one adverse event (AE). The most frequent AE
        Sa




Leishmania spp. in PBS supplemented with Rehydragel and                                was injection site related, and included the following:
4 mg/ml of gentamicin. The placebo dose contained .125 ml                              pain 43%, nodule formation 23%, heat 21%, and erythema
of Rehydragel in .5 ml of PBS; the same amount of alumina                              14%, as previously published.51Á54 When baseline PASI
is present in the 500 mg dose of the polyvalent vaccine.                               values in the group with PsA (n 0508) were compared with
Each step in the preparation of the immunogen was                                      posttreatment values, clinical remissions were: PASI 100
checked for sterility as previously published.51Á54 The con-                           in 275 (54.1%), PASI 75 in 117 (23%), PASI 50 in 73
centration of alumina was .25 ml per mg (v/w) of parasitic                             (14.4%), and PASI 10 in 43 (8.5%) of subjects, respectively.


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The Journal of Clinical Rheumatology and Musculoskeletal Medicine



The average number of AS100 doses required to induce                      Column statistitics between 19 values in PsA and skin
100% remission of psoriasis was 9.994.8.52                              psoriasis comorbidities frequencies were significant. D’Agos-
                                                                        tino & Pearson omnibus normality test had p B.0001 (two
Single Blind Trial With AS200 (L.(V)brasiliensis) and                   tailed), a similar p value found with the Wilcoxon Signed
an Active Control (AS100)                                               Rank Test (significant a value 0.05). One sample t-test
  All subjects had PASI scores determined prior to treat-               had p0.0019 with 95% CI of discrepancy from 2.055 to
ment, prior to each injection, and at follow-up for two                 7.661 for PsA and p 0.0079 with 95% CI of discrepancy
weeks after the last injection Of the 51 subjects treated, 45%          from 1.063 to 6.116 for psoriasis (a value 0.05 for both
experienced no AEs, of the AE observed, most were local                 columns).
in nature. The most frequent AEs of a local nature were
injection site pain (39%), erythema (12%), heat (12%), and              Clinical Regression of Skin Lesions in AS100 Trial
nodule formation of a short duration (8%). The most                       The first sign of clinical regression in skin psoriasis
common events of a systemic nature were general discomfort              after treatment with leishmania antigens polyvalent vaccine
(6%) and/or a low-grade fever (16%), sleepiness (6%), and               AS100-1 is the disappearance of itching followed by signifi-




                                                                                      C
headache (4%). Almost all AE were characterized as mild                 cant decrease in redness in the plaque from the periphery
or moderate. No AE was rated as ‘‘serious.’’ KruskalÁWallis             to the center (Figure 1a), from the center to the periphery,
                                                                        (Figure 1b) indicative of a gradual decrease in angiogenesis,




                                                                                   LL
test between the six Lb AS200 (Lb) treatment groups and
AS100 control had a p 0.495, and no significant variation               until the whole plaque is white without redness (Figure 1c).
between medians (p 0.05) was observed. Student’s t tests
comparing PASI reduction in each of the six treatment                   DISCUSSION
arms and the active control resulted in a nonsignificant                  We believe that the development and maintenance of
difference (average p 0.3109.22). All AS200 (Lb) vaccines                al,
                                                                        psoriasis and PsA since the beginning of lesions is centered
induced PASI reductions in the same range as the active                 in the blood vessels’ behavior. Both diseases start with
control.54                                                              redness in the skin and joints by proliferation of blood
                                                                        vessels and angiogenesis after up-regulation of VEGF and
Analysis of Comorbidities in Patients With Psoriasis
                                                            dic
                                                                        TGFb and other angiogenic factors. TNFa is a key cytokine
and PsA                                                                 in the inflammatory process because it activates EC, leading
  Comorbidities are presented (Table 1) in decreasing percen-           to expression of adhesion molecules, VCAM1, ICAM1, and
tages of frequency in PsA and compared with the frequency               E-selectin, opening the door to cells migration to sites of
in patients with psoriasis. Less than 1% frequency in                   inflammation.27 A multimolecular complex named immuno-
                                                 Me


both groups was found in the following comorbidities:                   logical synapse is formed between antigen presenting cells
Hepatitis, Glaucoma, cataracts, amaurosis fugax, prostate               (APC) and T cells. At the beginning of lesion formation, APC
hyperplasia, prostatitis, inguinal hernia, pitiriasis versicolor,       travel from the skin to the lymph nodes and after activation,
or alba, hypercholesterolemia, depression, anxiety, psycho-             CD4'CD8 (, CD3'CD8 (, CD8'CD3', CD8'CD4 (,
sis, vitiligo, obesity, alcohol consumption, intercostals neur-         and CD8'HLA ( decreased in PBMC as PASI increased,
itis, herpes zoster, anemia, Down syndrome, lipomas,                    suggesting migration from the blood to the skin. Contrary to
                                      as




HIV', amebiasis, leishmaniasis, and toxoplasmosis.                      the previous finding, the following LS: CD8'HLA' and
  The morbidity statistics in Venezuela were very scarce,               HLA'CD8(, and membrane surface immunoglobulin
only small groups in several localities could be found.                 IgA', IgD', and IgM' increased in PBMC as PASI
Values were 22%Á23.3% for HTA (n 0952), .17%Á.65%                       increased, suggesting activation and proliferation by un-
                   uc




for vascular diseases, and 4.4% for diabetes (n 0669).                  known antigens, maintaining a cycle between skin and
                                                                        peripheral blood.53 A different picture was observed in PsA,
For comparison, the mortality percentages in 2008 were
                                                                        CD4', CD8'HLA (, CD8'HLA', CD8'CD3 (, CD8'
included, the only statistics published so far in last five
                                                                        CD3' decreased in PBMC as PASI increased, suggesting
years. Higher percentage frequency in PsA (underline) than
                 nL




                                                                        migration from the blood to the skin. On the other hand, the
psoriasis patients was found in HTA, vascular diseases,
                                                                        following LS: CD8'CD4(, CD3'CD8(, HLA'CD8 (,
intestinal diseases, infections, gastritis, cardiac arrhythmia,
                                                                        CD19, CD8'CD4', and membrane surface immunoglobu-
gallstones in gallbladder, osteoporosis, hyperuricemia, and
                                                                        lin IgA', IgD', IgM', IgE', and IgG' increased in
epilepsy (Table 1).
                                                                        PBMC as PASI increased, suggesting activation and prolifera-
       Sa




  Several comorbidities were found in both psoriasis and                tion by unknown antigens creating a homeostatic cycle
PsA patients in several cases up to 7Á8 comorbidities together          between skin/joints and peripheral blood.52 After treatment
in the same subject (Table 2). This fact points out that                with leishmania antigens, both homeostatic cycles are
psoriasis is a systemic disease, induced by inflammatory                stopped, by many possible mechanisms under study, to
cytokines in all organs of the body being expressed in                  explain PASI decrease and clinical remission of lesions.
each tissue according to genetic and environmental factors              One first mechanism may be blocking the CD2' recep-
due to shared inflammatory pathways.                                    tor in the immunological synapse and subsequently the


JCRMM 2011; 2:(2). Month 2011                                       6                                      www.slm-rheumatology.com
                                                                                                                                              Psoriatic disease




                                                                                                   C
                                                                                                LL
                                                                                     al,
                                                                     dic
                                                       Me
                                          as




Figure 1. (a) Patient # 1291, male, 43-years-old, eight years with plaque psoriasis, no comorbidities, initial PASI 7.1, at dose 5 PASI 1.2, started decrease in
redness in the center and periphery of plaques. (b) Patient # 2427, female, 55-years-old, no comorbidities, initial PASI 8.6, at dose 8 PASI 5.6 started decrease in
lesions at the center of plaques. (c) Patient # 2593, male, 18-years-old, with plaque psoriasis, initial PASI 10.4, no comorbidities, PASI at dose 8 1.0 total
disappearance of redness in the plaques.
                   uc




inflammatory process in skin and joints as postulated                                mechanisms of most therapeutic products used today.
previously.51Á53                                                                     In our studies, we have postulated that antigenic fractions
  All mentioned comorbidities in psoriasis and PsA have                              could be stimulating regulatory CD8' T cells in skin,
                                                                                     synovium, and vascular wall lesions; an alternative mechan-
                 nL




a common cause, an inflammatory process in the respective
organs. The old hypothesis of passive lipid artery accu-                             ism to the inhibition of the immunological synapse, to
mulation has been substituted by low-grade inflammatory                              control the inflammatory process in the affected tissues
activity in the vascular wall, key in the pathogenesis of                            mentioned above.52,54,57
atherosclerosis. CVD present endothelial dysfunction35 with                            The inflammatory component of atherosclerosis involves
     Sa




formation of early fatty streaks. T cells (20%) are found                            cellular and humoral immunity to the phylogenetically
surrounding the plaque and in the fibrous cap, pointing                              highly conserved antigen heat shock protein 60 (Hsp60)
to a role of immunity in atherosclerosis similar to the                              postulated as the autoantigen initiating mechanism in
process in psoriasis skin and PsA joints.40,41,45 In our work,                       atherosclerosis that might play a role in triggering an
we found DEAE fractions from leishmania amastigote anti-                             autoreactive T-cell response. The first cells invading the
gens, suppressing psoriasis by stimulating lymphocytes, a                            intima have been identified as Hsp60-reactive T cells,
mechanism of action contrary to the immunosuppressive                                followed by macrophages and SMC.41 Leishmania antigens


www.slm-rheumatology.com                                                         7                                           JCRMM 2011; 2:(2). Month 2011
The Journal of Clinical Rheumatology and Musculoskeletal Medicine



are produced after a heat shock in promastigotes that               systemic disease by inducing regulatory T cells in peripheral
become amastigotes in a liquid culture medium.58 The                tissues in psoriasis and PsA.52,54,57
molecular weight of leishmania vaccine AS200 is similar to            Another relevant point to consider is that amastigotes
the range of most Hsp host ligands (50Á70 kDa) for TLR2             inhibit antigen presentation by repressing the expression
and could be competing with peptides in RASF receptors              of Class I and Class II MHC gene products, both basally
or Hsp60 reactive T-cell receptors in the vascular wall,            and following stimulation with IFNg.62,63 On the other
another mechanism suggested for inhibiting the inflamma-            hand, macrophages infected with L(L)major may express
tion of psoriasis, PsA, and CIA.54,57 Further support for           normal levels of MHC class II molecules, but parasites
T-cell cross-recognition of Hsp regions shared by the host          inhibit antigen presentation by interfering with the loading
and pathogen comes from epitope-mapping studies with                of antigens onto the MHC class II molecule.64 An alternative
a T-cell clone derived from mice primed with mycobacterial          suppression technique used by several leishmania species
HsP60. Data from several arthritis models such as adjuvant
                                                                    is to sequester the MHC II molecules and/or antigens
arthritis and collagen type II-induced arthritis favor a role
                                                                    within the phagolysosome.65 This is another probable
for Hsp60 autoimmune T cells in disease protection.59
                                                                    mechanism to explain the effect of leishmania antigens




                                                                                  C
To induce CIA, complete Freund’s adjuvant and M. tuberculosis
                                                                    from AS100 and AS200 vaccines on psoriasis and PsA.
was used; it is possible that treatment with leishmania
                                                                    They could be inhibiting MHC molecules in APC inducing
vaccine AS200 is acting in a beneficial way similar
                                                                    subsequent deactivation of the synaptic complex formed




                                                                               LL
to mycobacterial Hsp60 epitope cross reacting with self-
                                                                    with autoreactive T cells, stopping the inflammatory process
determinants, and also by competing with ligands for TLR2
                                                                    by the unknown psoriasis and PsA antigen.
thereby, decreasing CIA as found in our work, a model
for human RA.57,60                                                    Iridocyclitis (acute anterior uveitis) represents the most
                                                                    frequent extra-articular feature in psoriasis with an estimated
  Intra-abdominal fat is not an inert mass of tissue but
                                                                    prevalence of 2%Á25% of cases, characterized by inflamma-
                                                                     al,
a vigorous endocrine organ, secreting bioactive proteins
                                                                    tion of the anterior chamber with presence of leukocyte
promoting inflammation. Chronic inflammation in obesity
                                                                    precipitates; another example of the systemic inflammation
(BMI ] 30 kg m (2) is promoted by secretion of cytokines
                                                                    in psoriasis.12 Double blind trials must be performed to
such as: TNFa that induces insulin resistance by increasing
                                                                    analyze the effect of amastigote antigens on this comorbidity.
                                                         dic
free fatty acid production, leptin that stimulates T cells,
(IL)-6, and adiponectin. In this process, a balance is produ-         The NFkB pathway is one of the main signaling pathways
ced by adiponectin that reduces TNFa production, monocyte           activated in response to proinflammatory cytokines, inclu-
cell adhesion, macrophage phagocytic activity, and transfor-        ding TNFa, IL-1, and IL-18 as well as by ligation of the
mation of macrophages to foam cells.61 In our work, we              TLR by the pattern recognition of PAMPs. The NF-kB
                                              Me


found that leishmania amastigote antigens decreased produc-         pathway induces genes encoding proinflammatory cytokines,
tion of TNFa, IL-1b, CRP, complement 5a (C5a), and PASI             adhesion molecules, chemokines, growth factors, and
values in human psoriasis. This effect is similar to adipo-         enzymes such as COX2 and iNOS. A substantial number
nectin, and is another possible mechanism to explain                of similar proinflammatory cytokines are also found in
decrease of inflammation in psoriasis and PsA after vaccina-        skin psoriasis, PsA synovium, and EC of human athero-
tion with the amastigotes vaccine.57,60                             sclerotic lesions.40 In our work, inflammatory markers
                                   as




                                                                    CRP and C5a decreased significantly in serum after treat-
  TNFa plays a central role in the defense against intra-
                                                                    ment with six doses of AS200 DEAE leishmania amastigote
cellular infections with leishmania, a disease, that ends
                                                                    antigens. The leishmania antigens decreased markedly the
fatally in TNFa(/( mice. Resolution of an established
                                                                    TNFa concentration in supernatants from PBMC from
infection is mediated by IFN-g produced by CD4' T cells
                  uc




                                                                    psoriatic patients.60 In mice ConA-induced hepatitis, leish-
in C57BL/6-resistant mouse strain. In contrast, BALB/c
                                                                    mania antigens decreased serum TNFa and IL-1b compared
susceptible strain develops anti-inflammatory IL-4 and
                                                                    with placebo inducing significant reduction of CIA.57,60
IL-10 mediated CD4' T cell response with dissemination
                                                                    It would be interesting to determine urinary excretion of
of parasites and animal death. Analyses of immune responses
                nL




                                                                    nitric oxide by iNOS in psoriasis and PsA as a marker
in natural and experimental (healthy human volunteers)
infections show that the clear Th1/Th2 T cell responses             for the evolution of the disease before and after treatment
to L(L.)major seen in murine studies do not occur. Instead,         with amastigote antigens.
a typical mixed Th1/Th2 response is observed with PBMC                Diabetes mellitus and HTA frequency increased in PsA
from patients secreting varying amounts of IFNg, IL-10,             patients together with CRP level, platelet, and white cell
       Sa




and IL-4 depending on the clinical stage of the disease.60          counts. Inflammation, as reflected by the CRP level, was
In our work, TLCK-treated and NP-40-extracted amastigote            associated with a higher BMI, waist circumference, systolic
antigens contrary to live parasites induced decrease of             and diastolic blood pressure, sugar and insulin resis-
TNFa and inflammatory markers. The parasite antigens                tance, dyslipidemia, and increased thrombotic tendency.37
did not induce humoral immunity in psoriatic patients up            As explained above, we found CRP and C5a decreased
to six doses of AS100.51 This suggests that cellular immunity       significantly in serum after treatment with six doses of
is another alternative mechanism for control of psoriatic           AS200 DEAE leishmania amastigote antigens. Double blind


JCRMM 2011; 2:(2). Month 2011                                   8                                       www.slm-rheumatology.com
                                                                                                                               Psoriatic disease



clinical trials must be done to confirm their effect in these        TNFa, IL-1b, CRP, complement 5a (C5a); inhibition of
comorbidities.60                                                     MHC molecules in APC inducing subsequent deactivation
  It is clear that all the comorbidities have as substratum,         of the synaptic complex with autoreactive T cells; and
an inflammatory process in the respective tissue, due to             blocking VEGF receptors preventing proangiogenic signal
a cytokine cascade, similar to the immunological process             transduction and angiogenesis by VEGF cytokine.
found in skin psoriasis and PsA joints, starting by inflam-
mation in vascular structures with key changes in the                ETHIC COMMISSION
endothelial intima, a process that can be stopped with                 The clinical investigations were conducted in accordance
leishmania antigens as found in our work.                            with the Declaration of Helsinki. The Ethic Commission of
  The first sign of clinical regression in skin psoriasis            the National Academy of Medicine of Venezuela approved
after treatment with leishmania antigens polyvalent vaccine          the protocols for the field trial for leishmaniasis as well
AS100-1 is the disappearance of itching followed by signifi-         as the trials for psoriasis. Dr Blas Bruni Celli was appointed
cant decrease in redness in the plaque from the center to            as trial monitor and oversaw all subsequent follow-up
the periphery, or the periphery to the center (Figure 1a, b),        work on the trials. All volunteers signed an informed




                                                                                   C
indicative of a gradual decrease in angiogenesis until the           consent authorizing treatment.
whole plaque is white without redness (Figure 1c). It is               Acknowledgements: We would like to thank Dr Jose Rafael Lopez




                                                                                LL
noteworthy that the regression of lesions begins at the              Padrino, Professor at Harvard University, for critical discussions, and
blood vessels, the vascular tissue origin of the plaques             for suggesting useful ideas for the article, and to Dr Jose Felix Oletta
where lesions started. Probably, leishmania antigen peptides         for providing the data on prevalence and mortality of diseases in
blocked VEGF receptors preventing proangiogenic signal               Venezuela. Jose A. O’Daly Astralis CSO, CEO and Chairman, would
transduction and angiogenesis by VEGF cytokine. This effect          also like to thank The Technology Business Tax Certificate Transfer
                                                                     Program of the Greater State of New Jersey, Economic Development
is helped by decrease in CRP, C5a, TNFa, in patients and             al,
                                                                     Authority (eda) for their support.
also TNFa, and IL1b in ConA-induced hepatitis in mice,
after treatment with leishmania antigens, all cytokines                Disclosure: The authors declare no conflicts of interest.
involved in PsA, Psoriasis, and comorbidities.60
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