Review

Potential Therapy for Rheumatoid Arthritisand Sjogren Syndrome With HumanChorionic Gonadotropin

C. V. Rao, PhD1

AbstractAutoimmune diseases such as rheumatoid arthritis (RA) and Sjogren syndrome (SS) ameliorate during pregnancy, throughdampening (immunotolerance) of the maternal immune system which protects the fetus from rejection. A large number of studieshave shown that human chorionic gonadotropin (hCG) contributes to this tolerance. Studies on animal models have reaffirmedthat hCG treatment mimics the benefits of pregnancy. Based on the scientific evidence, randomized clinical trials comparing hCGwith current therapies and/or placebo are recommended for RA, SS, and for other autoimmune diseases such as, type 1 diabetesand ankylosing spondylitis, which also get better during pregnancy and hCG treatment seems to help.

Keywordshuman chorionic gonadotropin, rheumatoid arthritis, Sjogren syndrome, autoimmune diseases, pregnancy, fetal rejection,immunotolerance, cells of the immune system

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease in which

body’s immune system mistakenly attacks joints, instead of

attacking bacteria and viruses.1,2 Small and large joints of

hands and feet are usually affected.1,2 They become inflamed,

swollen, stiff, reducing the mobility and quality of life. Comor-

bidities include cardiovascular disease, infections, mental

health conditions, and malignancies.3 According to the US

Center for Disease Control and Prevention and Arthritis Foun-

dation, about 1.5 million people have the disease and the num-

ber of new cases appear to be increasing.4,5 Early diagnosis and

treatment are key to the prevention of further bone, cartilage,

and other organ damage. Left untreated, RA can lead to perma-

nent joints damage, disability, and even death due to involve-

ment of other organ systems.6

Sjogren syndrome (SS) is also an autoimmune disease in

which multiple exocrine glands, such as lacrimal and salivary

glands, which provide tears and saliva, are affected.7 As a

result, their secretions markedly decrease, resulting in distres-

sing dryness of eyes and mouth. Respiratory tract and vagina

can also become dry. The risk of developing lymphoma

increases by about 40-fold, and peripheral and central nervous

system can also get involved. According to 2014 Arthritis

Foundation report, approximately 4 million Americans have

this disease, which makes it the most prevalent autoimmune

disease.

The combined numbers of RA and SS will be much higher

worldwide. There is no known single cause, but prevailing

theories suggest that a combination of genetic and environmen-

tal factors play a role in triggering the immune system into

overdrive.1,2 High human and economic costs are associated

with these diseases.8-10 Human cost includes, chronic pain and

suffering, too sick to work, which results in job loss and health

insurance. The economic cost is the long-term use of immuno-

suppressive and anti-inflammatory drugs, some of which can

be quite expensive. The prevalence of both these diseases is

higher among women than in men.11 Both RA and SS fre-

quently occur together (Sjorgren Syndrome Foundation). The

current therapies use immunosuppressive synthetic glucocorti-

coids, nonsteroidal anti-inflammatory agents, and nonbiologic

disease-modifying antirheumatoid arthritis drugs (DMARDs)

to relieve the symptoms, slow the disease progression, and

reduce further tissue damage. Some of these drugs have devas-

tating side effects. Thus, there is a clear need for anything that

might reduce treatment costs and the toxicity of the drugs.

1 Department of Cellular Biology and Pharmacology, Molecular and Human

Genetics and Obstetrics and Gynecology, Reproduction and Development

Program, Herbert Wertheim College of Medicine, Florida International Uni-

versity, Miami, FL, USA

Corresponding Author:

C. V. Rao, Department of Cellular Biology and Pharmacology, Molecular and

Human Genetics and Obstetrics and Gynecology, Reproduction and Devel-

opment Program, Herbert Wertheim College of Medicine, Florida Interna-

tional University, Miami, FL 33199, USA.

Email: crao@fiu.edu

Reproductive Sciences2016, Vol. 23(5) 566-571ª The Author(s) 2015Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/1933719115597765rs.sagepub.com

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Paradigm Shift on the Human ChorionicGonadotropin Actions

Human chorionic gonadotropin (hCG) is a hallmark hormone

of pregnancy. It has a typical pregnancy profile, in which the

levels exponentially increase during early pregnancy, reaching

a peak by about ninth week, followed by a rapid decline to a

lower steady levels and remain there until the end of preg-

nancy.12 Self-regulation of hCG biosynthesis, involving both

positive- and negative-feedback mechanisms, could explain

this profile.13-16 While profiles remain relatively constant, the

absolute hCG levels could vary a great deal among individuals

and in different pregnancies of the same individual.12

Until about 1990, hCG was only considered to rescue corpus

luteum from regression in a fertile cycle and maintain its pro-

gesterone secretion, until placental shift of its synthesis is com-

pleted by about the ninth week.12 Thereafter, hCG was

considered a vestigial hormone. This textbook description of

hCG had begun to change with published data from around the

world, which showed that functional hCG receptors, which also

bind its structural and functional homolog, luteinizing hormone

(LH), are also present in many maternal and fetoplacental

tissues.17-20 Some of these tissues include, reproductive tract,

placenta, fetal membranes, decidua, several fetal tissues,

vasculature, and the cells of the immune system, such as regu-

latory T cell (Tregs), monocytes, macrophages, and dendritic

cells.17-24 Although much remains to be investigated, it is

becoming increasingly clear that hCG is a pleiotropic hormone,

whose actions are likely to be important for an initiation and

maintenance of pregnancy.17-20,25 At the end, it also seems to

have a permissive role in normal labor progression.25-29 The

initiation and maintenance of pregnancy likely involve many

hCG-driven changes in maternal and fetoplacental tissues. One

of them is the prevention of fetal rejection by the maternal

immune system.30-39 This wealth of findings opened new pos-

sibilities of hCG use to increase the implantation and clinical

pregnancy rates of in vitro fertilization procedures and to treat

several pregnancy complications.17-19,40-54

Evidence Linking hCG to Potential Therapyfor RA and SS

The first clue came from the clinical observations that the

symptoms of RA and SS ameliorate during pregnancy.55-60 The

RA flares up during the postpartum period, especially after

the first pregnancy, which was thought to be due to hormonal

changes and/or to the exposure to paternal HLA antigens.61

Theoretically, the benefits can accrue from any of the preg-

nancy hormones. Some of them increase, while others decrease

and the onset of changes vary with the hormone.12 The evi-

dence pointing to hCG came from the findings that it has

immunosuppressive and anti-inflammatory properties, which

current therapies target.62 Two animal models have been used

to test the effectiveness of hCG.

The first model was streptococcal cell wall (SCW)-induced

arthritis in nonpregnant rats.63 When SCW was injected, the

animals develop the signs and symptoms of RA within 2 days,

which resemble human disease. These include, swelling,

erythemia, and distortion of wrist and ankle joints; infiltration

of proinflammatory cells into the joints, bone, and cartilage

destruction; and the increased production of tumor necrosis

factor (TNF) a, interleukin (IL)-6, IL-1b, nitric oxide (NO),

and inducible nitric oxide synthase (iNOS). Injection of either

clinical grade or recombinant hCG, 2 days before the SCW

injection, resulted in a dose-dependent decrease in the develop-

ment of arthritis, blocked pathogenic changes typically associ-

ated with chronic disease phase, amelioration of symptoms,

decreased infiltration of proinflammatory cells, cytokines,

NO, and iNOS levels, bone, and cartilage destruction. While

the dimer hCG had dramatic suppressive effects, the isolated

a and b subunits had minimal effects, unless their doses are

increased by about 4-fold.

Nonobese diabetic (NOD) mice are common models for

autoimmune diseases research, including SS.64 These mice

show a decreased salivary flow, invasion of CD4þT, and B

lymphocytes into their salivary glands by 12 to 24 weeks of

age. These changes are very similar to those seen in salivary

glands of patients with SS. The hCG treatment from 6 to 12

weeks age resulted in a marked increase in salivary secretion

and a significant decrease in lymphocytes infiltration, damage to

salivary gland parenchymal cells, and a decrease in interferon g,

TNF-a, IL-1b, IL-10, iNOS, and matrixmetalloproteinase-9

levels.64

Scientific Basis of Therapeutic Benefit of hCG

Pregnancy is an immunotolerant state in which fetus is pro-

tected from an attack by the maternal immune system. A large

number of studies have now shown that hCG contributes to this

tolerance.30-39 Although, many knowledge gaps remain in the

complete understanding of how hCG works, it is widely recog-

nized that the same mechanisms are likely at work in protecting

the fetus as well as in providing the benefit against of RA and

SS. The published studies have shown that hCG uses the fol-

lowing mechanisms.

1. Pregnancy is a type 2 T helper (humoral immunity)

dominated state, which is induced by hCG from type

1 T helper (cell-mediated immunity) state.62

2. Increasing hCG levels coincide with the development of

immunotolerance at the local tissue and systemic lev-

els.15 At the local level, hCG increases the number of

uterine natural killer cells and induces the apoptosis

of T cells in decidua through Fas/Fas-ligand system.65

In addition, hCG promotes the function of macrophages

to clear apoptotic cells and to resolve the inflammation

and act to upregulate endometrial C3 and C4A/B gene

expression to modulate decidual immunity66,67

3. The hCG also upregulates at local level indoleamine

2,3-dioxygenase in syncytiotrophoblasts and in dendritic

cells which degrades tryptophan.68,69 This degradation

removes the proliferative stimulus for the effector cells

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at maternal–fetal interface and also their activation. As a

result, these cells cannot attack fetal tissues, thus sparing

the fetus from rejection.70 Further corroborating evi-

dence showed that coculture of syncytiotrophoblasts

with allogeneic lymphocytes induces an apoptosis in T

cells, and hCG treatment enhances this process.68-71

4. At systemic level, hCG treatment increases levels of

IL-10 and anti-inflammatory cytokine IL-27 and reduces

proinflammatory cytokine IL-17.72

5. Systemic immunotolerance also involves the expansion

and migration of Tregs to maternal–fetal interface by

hCG.72,73

6. In addition, hCG also induces the expansion of regula-

tory B cells. The expansion increases IL-10 secretion

and decreases TNF-a production by T cells74,75

7. Treatment with hCG enhances the mobilization of tol-

erogenic dendritic cells, induces the upregulation of

MHC class II antigens and IL-10 secretion, while keep-

ing nontolerogenic dendritic cells immature, tissue

bound, and promoted to undergo apoptosis.24,69,76

8. hCG injections can delay the rejection of allogeneic

skin grafts.72

The above-mentioned mechanisms are likely to be highly

integrated and coordinated in order to shelter the fetus from the

rejection and mother and fetus against the infections. While the

local and systemic mechanisms are important for pregnancy

continuation, the latter is likely to provide the benefit against

RA and SS.

Potential hCG Use for Other AutoimmuneDiseases

There are nearly 80 to 100 autoimmune diseases, with another 40

having some autoimmune basis. It is not likely that hCG will be

effective against all of them. In fact, pregnancy worsens the

symptoms of lupus erythematosus, an autoimmune disease,

which result from an increased antibody production by autoreac-

tive B cells.77,78 There are other autoimmune diseases, such as

type 1 diabetes, ankylosing spondylitis, multiple sclerosis, thyr-

oiditis, and Crohn disease, which also seems to improve during

pregnancy.60 Among them, hCG has been tested against ankylos-

ing spondylitis in men and type 1 diabetes in NOD mice.79-82

In both cases, hCG treatment has been found to be beneficial.

Why Does hCG Therapy Merit Consideration

The hCG, being a physiological hormone, has considerable

advantages over the currently used synthetic glucocorticoids,

nonsteroid anti-inflammatory drugs, and DMARDs. Some of

them can be quite expensive and come with severe side effects.

The hCG, by comparison, is not expensive and can be made

even cheaper by scaling up the production of recombinant hor-

mone. The hCG has minimal side effects and the commonly

described ones from the intramuscular injection are pain at the

injection site, abdominal bloating, abdominal and pelvic pain,

nausea, vomiting, and so forth, which do not often require med-

ical attention. If hCG is proven effective, there are many pos-

sibilities to improve upon how hCG can be administered. For

example, long-acting analogs and synthetic hCG mimetics for

oral use can be developed. Although, regular hCG cannot be

taken orally, due to its degradation in stomach, it can be taken

as lozenges, as hCG weight loss clinics promote. The active

ingredient, in a lozenge, would slowly dissolve and rapidly get

into buccal blood circulation. The hCG delivery by nanoparti-

cle is another potential area for development. The nanoparticle

delivery can reduce the dose and frequency of administration.

Based on the scientific data, randomized clinical trials can

be recommended. Potentially, there is much to gain from such

trials not only for RA and SS but also for other autoimmune

diseases such as type 1 diabetes and ankylosing spondylitis,

which also improve during pregnancy and hCG treatment

seems to help.79-82 It is possible that hCG may be effective not

only on its own but also work in combination with lower doses

of currently used drugs. Such combinations could be more

effective than single treatments, due to possible differences

in their modes of action. In addition, combination therapies can

save money and lowers the overall toxicity. As hCG is already

being used in reproductive medicine, it is possible to optimize

the treatment conditions with respect to the dose and treatment

frequency, rather quickly. In addition, the possibility of deli-

vering the lower doses of hCG directly into joint synovial fluids

of patients with RA can be explored. This route can reduce the

hCG dose and further minimize any side effects. The potential

hCG use for the treatment of RA and SS suggests that the hCG

administration for other clinical indications may change the

rate and progression of inflammatory/rheumatic diseases. This

possibility requires verification by further research. Until more

data become available, women with endometrial or ovarian

cancers or Alzheimer disease or with a strong family history

should be excluded from the hCG therapy because of the poten-

tial LH involvement in these diseases.83-89 Finally, as other

treatments, hCG therapy may not be a panacea, but it is likely

to become an important part of physicians tool box to treat

patients suffering with RA, SS, and few other autoimmune

diseases.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to

the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, author-

ship, and/or publication of this article.

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