website of interest: American College of Rheumatology
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that ultimately leads to the destruction of joint architecture. In rheumatoid arthritis, a person’s own immune system attacks the joints by activating the synovial tissue that lines the body’s movable joints, causing inflammation, swelling, pain and eventually erosion of the bone and cartilage and deformation of the joint. An estimated 1.5 million people are diagnosed with moderate or severe rheumatoid arthritis (RA). RA is one of the most common autoimmune inflammatory disorders, with a prevalence of between 0.5-1% in most adult populations.
Prevalence of RA is estimated to be 0.8 percent worldwide, with women twice as likely to develop the disease as men. Untreated, 20 to 30 percent of persons with RA become permanently work disabled within 2-3 years of diagnosis (Rindfleisch, American Family Physician, 72(6), 2005, 1037-1047).
Causes: Pathological Events
The pathogenic events that lead to the development of RA are not fully understood, although the pivotal role that proinflammatory cytokines (i.e., TNFalpha, IL-1beta, IL-6, etc) play in the induction and maintenance of this disease is well documented. Among the many genetic studies of small cohorts, the only genes consistently associated with RA are the MHC (i.e., human leukocyte antigen (HLA) linked genes, on the short arm of human chromosome 6. It has been estimated that about one third to one half of the total genetic contribution to RA can be attributed to genes within the HLA complex.
Deficiency in Complement Components:
Deficieincy of C1q, Clr, Cls or C4 is closely linked to defvelopment of rheumatoid arthrisis (as well as SLE) thought be be due in part to the inability of complement to clear immune complexes and dysing cells. Small complexes are cleaved from the circulation when they bind to complement receptors on macrophages in the speen and liver. Without complement, the complexes can grow too large to be easily cleared. The resulting aggregates can activate the alternative pathway, allowing C3 to be deposited into the matrix, with re-solubilized complexes that can be dealt with by the clearance through the liver and spleen. Failing this, these large complexes are no longer soluble and form deposits in the tissues and become a site of inflammation. Dying cells if not cleared by non-inflammatory CP activity, may serve as sources of altered self-antigens with the potential for inducing autoantibodies. (US Patent Applicaiton No: 15/895,551, published as US 2019/0247560).
Diagnosis
No single diagnostic test definitvely confirms RA. However, several tests can provide objective data that increase diagnostic certainty. The ACRSRA recommends that baseline laboratory evluations include a complete blood cell count with differential, rheumatoid factor, and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Baseline evlauation of renal and hepatic function also is recommended because these finding with guide medication choices (Rindfleisch, American Family Physician, 72(6), 2005, 1037-1047.
CD93 (C1qR): Crockard (Immunology Letters, 36 (1993) 195-202) disclsoses that levels of C1q receptor (C1qR) were significantly higher on synovial fluid neutrophils from patietns with rheumatoid arthritis compared to normal control subjects.
Young (WO/2010/087594 and US 13/146876) also discloses that CD93 soluble fragment in synovial fluid obtained from rheumatoid arthritis patients was significantly higher than that in synovial fluid obtained from osteo-arthritis patients and that the CD93 molecule or its soluble fragment can be effectively used as a diagnostic marker for RA.
Symptoms
Clinically, RA is a highly heterogeneous disease varying from very mild to severely disabling with upwards of 1 in 20 patients progressing to severe, erosive disease. Joint damage occurs early in disease with the greatest progression to joint abnormalities taking place during the first 6 years. Within 3 years of disease onset, as many as 70% of patients show some radiographic evidence of joint damage. The most commonly used diagnostic criteria are those adopted by the American College of Rheumatology in 1987. A pateint is classified as ahving RA if she has 4 of the following 7 criteria (i) morning stiffness lasting at least one hour (ii) arthritis of 3 or mroe joint areas (iii) arthritis of hand joints (iv) symmetric arthritis (v) rheumatoid nodules (vi) presence of serum rheumatoid factor (RF) and (vii) radiographic changes in hand or wrist joints.
Treatment Strategies
The American Rheumatism Association (ARA) recommends that patients with suspected RA be referred within 3 months of presentation of confirmation of diagnosis and initiation of treatment with DMARDS (see (1) below). In past decades, pharmacologic treatment of RA was managed using a pyramid approach with symptom alleviating treatment at the start of diagnosis. However, a reverse pyramid approach is now favored in which DMARDs are initiated quickly to slow disease progression as early as possible.
(1) Disease Modiyfing Anti-Rhematic Drugs (DMARDs): Many DMARDs have been used in the treatment of other diseases such as cancer and malaria. Antimalarial DMARDs include chloroquine (Aralen) and hydroxycholoroquine (Plaquenil). Other DMARDS include methotrexate (Rheumatrex) and TNF blockers such a sinfliximab, an IgG1 anti-TNFalpha antibody.
Cyclosporin A (CSA) has also been shown to be effective in treatment of patients with RA, although there are side effects such as renal toxicity, hypertension and gastrointestinal complains. In this respect, Hydroxycloroquine (HCQ) has been suggested as a better replacement (Seo, Ann Rheum Dis 2001, 60: 514-517).
Slow-acting antirheumatic Drugs (SAARDs) are a special class of DMARDs where the effects are slow acting.
(2) Immunosuppresive cytotoxic drugs: This class of drugs is used if treatment with NSAIDs and SAARDs have no effect. Examples include methotrexate.
(3) Complement Inhibition: The role of complement in the pathogenesis of animal models of human RA has clearly been demonstrated. For example, immunofluorescence data in rats with collagen-induced arthritis (CIA) showed that aricular cartilage contained IgG and C3. when rats were depleted of complement with cobra venom factor (CVF), the onset of clinical disease was delayed and the development of disease in thse animals correlated with the return of functional complement activity. (Goodfellow, Clin Exp. Immunol. 2000, 119, 210-216).
(4) Fusion Proteins: Many of the antibodies below and antibody fusion proteins work by pventing both T and B cell activation.
—CTLA4-Fc: A new drug called Orencia is a fushion of cytotoxic T lymphocyte antigen-4 (CTLA4) and a gradment of the Fc portion of IgG1 which purportedly blocks the costimulatory signal between antigen-presenting cells and T cells, preventing T cell activation has been approved by the FDA for the treatment of rheumatoid arthritis. Phase 3 results showed that half of Orencia patients who fialed traditional anti-TNF therapy acheived at least a 20% improvement in the signs and symptoms of the disease compared with one fifth of patietns receiving placebo. However, only one patient in ten experienced 70% improvement. Thus Orencia is a logical choice for those patients failing anti-TNF therapy. It is sold by Bristol-Myers Squibb.
–TNFR2-Fc:
Enbrel (entanercept): Amgen markers Enbrel® which is a fusion protein of the soluble portiion of human tumor necrosis factor receptor joined with the Fc region of IgG1 as a therapy for rheumatoid arthritis. US 8,063182 covers the entaercept protein itself and US 8,163,522 covers a method of producing it. The patents do not exprie until 2028/2029. Entanerceipt constitutes a soluble fragment of the 75 KD human tissue TNF receptor that is fused to the hinge, CH2-CH3 region of the H cahin of IgG. The purposted befit of the fusion prtoein is that fusing a receptor with IgG prtoeins yields increased affinity for the TNF antigen. The TNFr:IgG prtoein dimerizes adn therefore displays two copies of the receptor, thus increasing affinity. In addition, the half life of the fusion protein is also purportedly much greater than the TNF receptor alone.
Other novel treatments which will challenge dominance of TNF blockers such as Centocor’s Remicade (infliximab), Amgen/Wyeth’s Enbrel (etanercept) and Abbott’s Humira (adalimumab) are likely to follow. Rituxan, a B cell targeted chiermic antibody from Cambridge, MA-based Biogen Idec is also now in treals for RA. Another possible RA drug is Chugai’s anti-Il-6 MRA antibody, which is now in phase 3.
5) Antibodies against specific molecules:
–CD20 antibodies: anti-CD20 MAB (Rituximab) has been shown to effectively reduce B cell numbers and is being evlauted in hclinical trials for pateints with autoimmuen diseases.
-CD22 antibodies: is a B cell specifi c glycoprotein that first appears intracellularly during the late pro B cell stage of ontogency, with expression shifting to the plasma membrane with B cell meturation until plasma cell differentiation. CD22 deficient mice have hyperactivated B cells and CD22 deficiency is sufficient to predispose to development of high affinity autoantibodies in mice. The development of MABs that block CD22 engagement may have considerable benefit for treatment of autoimmunity (Tuscano, Autoimmunity Reviews 2 (2003) 101-108
–CD200 antibodies: Wang (12/452772) discloses that an anti-CD200 antibody lessened RA conditions in an arthritis animal model (collagen induced arthritis (CIA) mouse model strain from Jackon Labs). Bowdish (WO2007/084321) also discloses that anti-CD200 antibodies can be useful for treating autoimmune disease such as rheumatoid arthritis. Liversidege (US2007/0065438) also dicloses administration of an agonist or antagonist of CD200 such as an antibody that specifically binds to CD200 for treating a disorder such as rheumatoid arthritis.
–CD200R antibodies: Gorczynski (US 2005/0048069; US 2005/0107314) diclose that anti-CD200R antiboides reduce symptoms of established RA. The antiboides bind to and crosslink CD200 receptor which enhances the immune suppression caused by CD200.
–IL-1 antibodies: Joosten (Arthritis & Rheumatism) discloses that anti-IL1 alpha/beta treatment ameliorated both early and full blown collagen-induced arhtritis (CIA), which is a widely used experimental model of polyarthritis.
–TNF-alpha antibodies: such as infliximab and adalimumab have been shown to be very effective in treating RA. (See antibodies and therapeutic applications). The Biosimilars simlandi (adalimumab-ryvk) made by Alvotech and Teva Pharmaceuticals and interchangeable with Humira has also been approved. The biosimilar, a TNF alpha inhibitor was approved to be provided as a single-dose autoinjector delivering 40 mg/0.4 mL, for treating plaque psoriasis, Crohn’s disease, ulcertative colities, rheumatoid arthritis juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurative and uveitis.
(6) Glucocorticoids: Steroids at dosages equivalent to less than 10 mg of prednisone daily are highly effective for relieving symptoms of RA and can slow joint damage.
(7) IVIG: Weisbart (US2002/0098182) disclsoes treating immune mediated diseases such as RA by oral administration of Cohn Fraction II+III.
Alternative Medicine and Food Products as Treatment Options
(1) Green tea, called EGCG, reportedly inhibits production of several immune system molecules involved in inflammation and joint damage. It inhibits proudction of IL-6 and prostaglandin E2, the inflammatory products found in the connective tissue of people with rheumatoid arthritis. In one study by Dr. Ahmed, synovial fibroblasts (cells that form a lining of synovial tissue surrounding the capsule of the joints) were isolated from the joints of patients suffering from rheumatoid arthritis. EGCG was able to block IL-1bettas ability (the cells were stimulated with IL-1betta) to produce proteins and enzymes that infiltrate the joints of persons with rheumatoid arthritis.