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Modern Treatment of Rheumatoid Arthritis in Cows | OMICS International
ISSN: 2157-7579
Journal of Veterinary Science & Technology

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Modern Treatment of Rheumatoid Arthritis in Cows

Kalil MA*

Faculty of Medicine, Cairo University, Egypt

*Corresponding Author:
Kalil MA
Faculty of Medicine, Cairo University, Egypt
Tel/Fax: (202)23682030
E-mail: [email protected]

Received date: July 31, 2014; Accepted date: November 26, 2014; Published date: November 28, 2014

Citation: Kalil MA (2014) Modern Treatment of Rheumatoid Arthritis in Cows. J Veterinar Sci Technol 5:202. doi:10.4172/2157-7579.1000202

Copyright: © 2014 Kalil MA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Rheumatoid arthritis (RA) is a chronic autoimmune disease, which is thought to be one of the major public health problems in the world. The pathogenesis of rheumatoid arthritis is the topic of contemporary research. For most satisfactory outcome rheumatoid arthritis should be treated in early stage. Nevertheless, in spite of new progresses in rheumatoid arthritis medical therapy, their treatment still denotes an unmet medical requirement because of safety and efficacy anxieties through presently prescribed medications. The Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Glucocorticoids (GC) are employed respectively for the symptomatic and local therapy of rheumatoid arthritis. However the Tumor Necrosis Factor-α (TNF-α), Interleukin-1 (IL-1) and B cells have received increased interest resulting in numerous novel therapeutics. B-cell depletion agent (rituximab), Tumor Necrosis Factor-α inhibitors (etanercept, infliximab, and adalimumab), Interleukin-6 receptor blocker (tocilizumab), and T-cell co-stimulatory blocker (abatacept) are current biologics which are used as Disease-Modifying Antirheumatic Drugs (DMARDs) for the basic treatment of rheumatoid arthritis. Future treatments are consist of biosimilars, alternative Tumor Necrosis Factor-α inhibitors (golimumab and certolizumab), and kinase inhibitors (tofacitinib and fostamatinib).


Rheumatoid arthritis treatement; NSAIDs; Glucocorticoids; Biologics


Arthritis is a universal expression used to explain painful conditions of joints and bones. Spondylitis, osteoarthritis, rheumatoid, gout and psoriatic arthritis, reiter’s syndrome and lupus are different types of arthritis [1]. RA is an inflammatory disease that has an effect on synovial of joints, tendons, and usually a number of extra-articular sites [2]. This could lead to the damage and swelling of joints, pain, fatigue and development of co-morbidities like cardiovascular diseases. This structural and functional destruction of the body may result in restrictions in physical activities and limitations in participation [3]. It is mainly the universal form of chronic inflammatory arthritis. Constant synovitis, systemic inflammation, and autoantibodies are the characteristics of RA (predominantly to rheumatoid factor and citrullinated peptide). Women are two to four times more concerned than men (estimated female occurrence 24-60/100,000 in opposition to male 15-26/100,000 in the European and North American populations). Synovial and cartilage cells are the main cells population of joints, which affect through RA. This disease affects the 1-2% of the population [4,5]. Subcutaneous nodules, existence of rheumatoid factor (in almost 80%), and radiographically erosions or jusxta-articular osteoporosis in or closest to the involved joints are additional characteristics of RA. The prevalence of RA is more in advanced age, and the RA disease may found in 4% to 6% of with population older than 65 years. Though the cause of RA is unknown, evidence recommends an association among severe RA and HLA, especially to alleles coding for a shared epitope on the HLA-DRBI molecule [6]. The early morning stiffness (EMS), frequently lasting longer than 30 minutes, joint swelling (≥3 joints) and compression tenderness on ‘squeeze test’ across the metacarpophalangeal (MCP) or metatarsophalangeal (MTP) joints are the mains characteristics of RA [7]. The pathogenesis of RA is the theme of current research, however the function of TNF-α, IL-1 and B cells have received increased interest resulting in numerous novel therapeutics [1]. RA patients are more exposed to the risk for cardiovascular disease that is comparable to the risk in patients with type 2 diabetes mellitus; consecutively they need to be daily screened for mentioned disease. NSAIDs and oral Glucocorticoids are mostly recommended in RA that are both associated with the development of hypertension [8]. Typically, the criteria for the classification of RA relied on the existence of signs and symptoms which indicate the inflammatory activity that typically implied permanent structural damage while exist. This situation causes a new set of criteria for the classification approved by the European League Against Rheumatism (EULAR) and the American College of Rheumatism (ACR) to diagnose RA (Figure 1) [2].


Figure 1: Development phases of RA. In RA development representation model, the double-headed arrows point out that progression of RA may be stopped, or reversed, possibly through immunomodulatory pharmacologic intervention(s), particularly if initiated prior to the start of clinically apparent IA (Phase 4) [9,36].

Several of the strongest risk factors are certain genetic factors include the existence of human leukocyte antigen (HLA) alleles comprising the ‘shared epitope’, female sex, family history of RA and contact to cigarette smoke [9-11]. The aim of this paper is to evaluate the modern and basic RA treatment.

When to Start Treatment?

Recently, according to the recommendation of European League Against Rheumatism (EULAR) the RA therapy should begin after diagnosis. It has been shown that a delay in the start of treatment has an impact on the progression of radiological damage. While the treatment is started timely (in 12 weeks from start of symptom), the patients have better change to reply to the therapy and to achieve remission. Therefore, we are able to extrapolate that the treatment must be started at least within 12 weeks from the beginning of symptoms for most favorable outcome.

Therapeutic Modalities and Strategies

Relief of pain, stopping of disease evolution and prevention of disability are the objectives of the RA treatment [12]. RA treatment through a goal or “treat to target” strategy recommend that the therapeutic target in RA must be a state of remission or as substitute goal might be a low disease activity. Rheumatologists have to evaluate and record disease activity in each clinical appointment and if the aim has not been attained, adjustments in the therapy should be taken. It is also explained that applying protocolized treatment suggests larger outcomes and proposes the frequency of visits (monthly in several cases with clinical activity and each 3 months when the goal is reached) [2].

Symptomatic treatment

Non-Steroidal Anti-Inflammatory drugs (NSAIDs): The majority of NSAIDs are nonselective inhibitors of cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) [13]. Protection of the stomach inside layer from gastric acid erosion and many other normal body process controls by COX-I enzyme. Additionally the logical therapeutic aim is the inhibition of COX-II, which expressed more in inflammatory circumstances. The understanding of this issue points out that durable use of NSAIDs (non-selective COX-I and COX-II inhibitors) often provoke the digestive system bleeding and stomach ulcers. According to these facts, COX-II selective inhibitors to create less digestive system complications have developed and found [10]. A number of COX-II selective inhibitors were later recalled from the market as a result of unpredicted cardiovascular safety problems. For the improvement of the treatment by NSAIDs another issue to be taken into account is the in vivo organization of drug distribution. NSAIDs oral administration, have the small quantity of the drug that can be absorbed and get the arthritis joints [11]. Certain NSAIDs have been shown the myocardial infarction, stroke and cardiovascular death. It has been found that cardiovascular risks of NSAIDs are significantly different from each other. Generally, naproxen has been found less dangerous in consideration to the cardiovascular disease (CVD) in comparison to other NSAIDs [8]. The majority of NSAIDs comprise a carboxylic acid function, which admits direct carbodiimide combination of the drug to the pendent hydroxyl groups of dextran by the use of an ester bond. The stability of this ester bond because of the presence of plentiful esterase in the circulation is the major concerns [14]. To avoid the Gastric side effects by NSAIDs the authors also anticipated oral administration of prodrug without release of drug in the stomach but activate the prodrugs in the last part of ileum and colon through at hand glucosidases and hydrolases at these GI tract sections. After the experiments on healthy pig model absolute oral bioavailability of different conjugates of dextran derivatives – naproxen was found inside 83-106%, which is alike to the oral bioavailability of naproxen itself (90%). Through the amphiprotic compound (azapropazone) employment, the problem of NSAIDs – induced digestive system mucosal damage would be solved [15]. Because of the inadequate efficiency, lack of ability to modify the long-term course of illness, gastrointestinal and cardiac toxicity, the historical role of the NSAIDs as choice treatment of RA have been lost. The precise mechanism of action through which NSAIDs boost the risk of a cardiovascular event is not completely known. According to suggestions the inhibiting of COX-II play considerable role in the mentioned risk profile of an individual NSAID [8].

Local treatment

Glucocorticoids (GC): According to the clinical trials of high methodological quality that low-dose Glucocorticoids have a modifying effect of structural damage in early RA. As a result of the benefits which caused by inflammatory activity and its force on bone and lipid metabolism, their use in the first 2 years of RA appears practically safe [16]. The two principally useful settings of Glucocorticoids are: first short period usage in the time of flare-ups in disease which is able to lead immediate enhancement and permit other therapies like Disease- Modifying Antirheumatic Drugs having a slower onset of action to be adjusted. Second, to get very efficient local treatment for individual active joints. The arthritis suppression and joint destruction retard might be amplified while the intra-articular Glucocorticoids injections are a part of treatment strategy. In the first months of treatment the small dose (<10 mg prednisolone or equal) facilitate the control of synovitis and suppression of inflammation. To the majority of patients, the update proofs point out that biologic drug must reserve to patients not responding to early Disease-Modifying Antirheumatic Drugs treatment while used as combination therapy [17]. Corticosteroids are frequently applied in early disease, but their use is not a good long-term strategy for most patients.

Basic treatment

Disease-Modifying Antirheumatic Drugs (MDMARDs): Disease- Modifying Antirheumatic Drugs comprise Methotrexate(MTX), D-penicillamine, gold salts, sulphasalazine, anti-malarial drugs and immunosuppressant drugs (Cyclosporin, Glucocorticoids). According to harmony, treatment throughDisease-Modifying Antirheumatic Drugs is the greatest approach to suppress the evolution of RA. Since past few decades, clinical management of RA, particularly at the first period of the illness has considerably enhanced by Disease-Modifying Antirheumatic Drugs. Disease-Modifying Antirheumatic Drugs are also classified into traditional Disease-Modifying Antirheumatic Drugs (variety of synthetic small molecules) and biological Disease-Modifying Antirheumatic Drugs that produced by genetic engineering [6]. By parenteral route of administration the inflammation site can be target through the conjugation of the prodrug with macromolecular carrier (High molecular weight prodrug derivatives of anti-inflammatory drugs). Disease-Modifying Antirheumatic Drugs acts through different mechanism of action that is incompletely known. However, they decrease joint pain and swelling, reduce acute-phase markers, restrict the progressive damage of joint and enhance function. Methotrexate is the main Disease-Modifying Antirheumatic Drug [4]. The undesirable effects of the Disease-Modifying Antirheumatic Drugs are minor (e.g. nausea) and serious (e.g. hepatotoxicity, blood dyscrasias, and interstitial lung disease).

Prodrugs large molecule of traditional disease-modifying antirheumatic drugs: All traditional Disease-Modifying Antirheumatic Drugs which are different synthetic small molecules, away from the role of improving clinical and radiological results have extra-articular toxicities and as a consequence should regular monitor the safety concerns. Initially Methotrexate was developed for cancer treatment, but subsequently was revealed to be a slow acting but effective Disease- Modifying Antirheumatic Drugs in RA management. Up-regulation of the expression of extracellular adenosine (potent anti-inflammatory molecule) is the mechanism of action of Methotrexateas anti-rheumatic [6].

Only in evaluation of therapeutic efficacy in inflammatory arthritis animal models, albumin-based Methotrexateprodrugs have been used [18-20]. Moreover conjugate, for macrophage and dendritic cell-targeting delivery of Methotrexate a biotin-containing HPMA copolymer–Methotrexate prodrugs (Methotrexate-PHPMA-biotin) was developed. On the other hand, minimum information is accessible from in vitro or in vivo efficacy studies [21]. Further Methotrexate macromolecular prodrugs that have been developed for tumor treatment and their potential use in inflammatory conditions will as well confer in this part.

Macromolecular Methotrexate prodrugs developed for RA therapy: Albuminis the suitable carrier system for targeting delivery of drug into inflamed joints. It has the properties of tropism to inflammation and tumor area, long circulating half-life, lysosomal biodegradable properties, less toxicity and noimmunogenicity. As link among Human Serum Albumin and Methotrexate is a constant amide bond, which is not simply cleaved in the circulation [22].

Biologics: The B-cell depletion agent (rituximab), TNF-inhibitors (etanercept, infliximab, and adalimumab), Interleukin-6 receptor blocker (tocilizumab), and T-cell co-stimulatory blocker (abatacept) are present biologics. Upcoming treatments consist of biosimilars, alternative TNF-inhibitors (golimumab and certolizumab), and kinase inhibitors (tofacitinib and fostamatinib) [2]. TNF antagonists are assumed to apply their effects through interaction by inhibiting the soluble TNF-α with its endogenous membrane-bound receptors. With partial exceptions, all five agents have been studied and approved for the management of RA as monotherapy and in combination with Disease- Modifying Antirheumatic Drugs, in advanced as well as early RA.

As measured by suppression of radiographic progression and reduction in signs and symptoms, the combination of all five above agents with Methotrexate, are superior to Methotrexate monotherapy equally in advanced and early disease [23,24]. EULAR have recommended, beginning of the treatment with Methotrexate in the early RA [17]. According to the studied patients whohad already inadequate responses to Methotrexate, the efficacy of combination therapy compared to Methotrexate monotherapy is vigorousin advanced disease [25-27]. In comparison, early RA patients who are naive to Methotrexate treatment, the advantage of combination therapy of an anti-TNF agent plus Methotrexate compared to Methotrexate alone is considerably more modest [28,29]. Therefore, in clinical practice in patients with newly diagnosed RA, Methotrexate monotherapy or monotherapy with an alternate non-biologic therapy (e.g. sulfasalazine and leflunomide) is frequently used as first line therapy, and a TNF antagonist is added subsequently only if the response to Methotrexate (and/or other non-biologic Disease-Modifying Antirheumatic Drugs) is inadequate [30]. Initiation of a TNF antagonist as a first-line treatment of RA may occasionally be justified in patients with multiple risk factors for severe disease (e.g., high autoantibody tires, baseline radiographic erosions, and high levels of inflammatory markers) [31]. A distinct advantage of TNF inhibitors over conventional oral Disease- Modifying Antirheumatic Drugs is their rapidity of action, with clinical improvement evident in many patients within a week of initiation.

The injection site and infusion reactions are most common adverse events of TNF antagonists. Those are although occurring in up to 30% of patients. In clinical trials these reactions are in general managed with local steroids (for injectable agents) and by slowing the infusion rate and/or by pre-infusion administration of antihistamines or steroids (for infliximab) without any complication [24,26,28,32,33]. The increase of antibodies against both chimeric and fully human monoclonal anti- TNF antibodies is reported and this can decrease their long-term efficacy and increase the probability of an injection/infusion reaction (Table 1).

Agent Route Dosing Indication
TNF Inhibitors (MID Etanercept sq 50 mg weekly Moderate to severe RA
Infliximah iv 3 mg/kg at 0.2.6 necks, then every ft weeks thereafter: dose may be Increased to 10 mg/kg: Interval may be decreased to every • weeks. Administer with tnethOtrexate. DMARD naive RA Moderate to severe RA DMARD naive RA
Adalimumab sq 40mg every other week: Interval can be decreased to every week Moderate to severe RA DMARD naive RA
Golimurnab Sri 50 mg every month Moderate to severe RA DMARD naive RA
Certobzumabpegol sq 400 mg at 2.4 weeks then 200 mg every 2 weeks thereafter. 400 mg every 4 weeks is an alternative (or maintenance. Moderate to severe RA OMARD naive RA
Other approved biologics      
Ritaximab Iv 1000Ing at 0. 15 days then based on clinical symptoms (not more frequently than every 16 weeks) Moderate to severe RA. after failure of TNF antagonist
Abatacept Iv/sq Iv route: Weight based (<601r4:500mg. 60-100Kg: 750mg. >100KR:1000mg) at 0.2.4 weeks and then every
• weeks thereafter. SQ route: 125 mg weekly following
• Single Iv Manion ( lOms/ks)
Moderate to severe RA DMARD naive RA
Tocilizumals iv Draggles event 4 weeks. May be Increased to 8 mg/lCg (not to exceed 800rng per infusion). Moderate to severe RA. after failure & TNF antagonist
Investigational Drugs   Mechanism of Action Completed study stage
CP-690.550 (tofacitinib) PO AK 3 Inhibition Phase II
R788 ((ostamatinib) PO Syk Inhibition Phase II
Atacicept iv Anti- IlLyS/APSUL Phase II
AIN457 iv IL-17 inhibition Phase I/11
Orselizumab iv Anti-CD20 Monoclonal Antibodies Phase III
Ofatumumab     Phase 1/11
Apilimodmesylate (STA-5326)  PO 1L-12/11-23 Inhibition Phase 11 trials
Parnapimod VX-702  PO P38 MARK Inhibition Phase II

Table 1: Summary of FDA-approved biologics and current investigational drugs for the treatment of RA.

The boost threats of opportunistic infections (tuberculosis, histoplasmosis and others) developments are more considerable concern in TNF antagonist therapy [34,35].


Rheumatoid arthritis is a complex and most frequent chronic inflammatory disease. For optimum and basic treatment, timely diagnosis and appropriate therapy through Disease-Modifying Antirheumatic Drugs is obligatory. Non-Steroidal Anti-Inflammatory Drugs are widely used to control symptoms of rheumatoid arthritis. Moreover, for local treatment of rheumatoid arthritis Glucocoriticoids have been used but for fundamental treatment of rheumatoid arthritis, Methotrexate is the initial therapy and, while there is inadequate response or adverse reaction, is pursued by adding combinations of other Disease-Modifying Antirheumatic Drugs. Based on certain proves, if the treatment is begun in 6 months (or better, in 12 weeks) since the starting of symptoms relatively, the therapy has better outcome than further delayed onset. Each type of therapy must follow certain specific objectives which includes; alleviation of pain, prevention of disability and stopping of disease evolution and the rheumatoid arthritis treatment should not limit only with symptomatic therapy. In addition to clinical measures of disease activity, radiographs can help to evaluate joint space narrowing and bone erosion to determine efficacy and results. Kinase inhibitors presently under investigation for the treatment of rheumatoid arthritis which include tofacitinib and fostamatinib. Moreover, for determination of biomarkers to allow the choice of treatment strategies and determination of the proper approach to continue the treatment in patients who attain clinical remission, there may be need of further specific researches.


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