Rheumatoid Arthritis (RA) is a chronic autoimmune disease which involves many body systems and multiple joints. RA symptoms include; stiffness, pain, swelling and restricted mobility [1-7]. The many steps of RA development begin from the synovium, a membrane or protective sac around the joint which contains the lubricant synovial fluid. Besides cushioning, the fluid supplies oxygen and other nutrients to the slippery collagen tissue of cartilage at the end of bones. The abnormal immune reactions in RA produce a destructive molecule that slowly destroys cartilage collagen, shrinks joint space and then causes bone damage [8-10]. Cartilage destruction is accelerated by fluid accumulation and immune system cells present in synovial fluid. This occurs in progressive RA and leads to the creation of a thick synovial tissue called pannus [8, 12]. The pannus generates more enzymes that further damage nearby cartilage and worsens the condition by more inflammatory white cell attraction [12].

Considerable research looking to identify the specific mechanism of raised inflammation which causes tissue destruction in arthritis has been done with very little success yet [13]. Regarding research on RA-related pathophysiology, the development of RA seems to occur in a complex series of procedures.

Recent epidemiologic research suggests that almost 1% of the world’s population suffer from RA. And this greatly affects the general quality of life. RA is also more prevalent among women and is usually developed between the ages of mid 40’s to late 50’s (about 80% of all cases). Treatment for RA involves medication plus lifestyle alterations. Steroids (cortisone injection) and non-steroidal anti-inflammatory drugs (NSAIDs) are usually provided as conventional treatment [24]. However, these drugs only ease the pain. They lack tissue repair properties. A wide spectrum of drugs are used in retarding RA progression while managing the pain, but none completely cures the diseases. Moreover, RA patients taking NSAIDs regularly are usually diagnosed with stomach ulcer [25, 26]. Patients are often pushed by these adverse side effects to get complementary and alternative treatment (CAM) [27]. A study recently conducted on RA patients shows that 60-90% of them use CAM, implying that those in chronic pain plus the others not happy with allopathic treatment have high chances of looking for alternative medicine [28]. This highlights the importance of a reliable alternative to eliminate the issues of current allopathic treatment.

After looking at the plant list in Table 1, it can be concluded with scientific backing that Aloe barbadensis has a vital role in the reduction of RA related pain and inflammation [33].

The most biologically active of all 400 aloe species is Aloe barbadensis Miller [syn. Aloe vera (L.)].

Although standardization is still lacking, certain specifications are required for Aloe barbadensis products to be certified by the international trade association, the International Aloe Science Council (IASC).

The specific mechanism by which rheumatoid arthritis-related pain, wound, and inflammation are eliminated by Aloe barbadensis is yet to be explored. Many in vitro and in vivo experiments have been conducted to identify the main active components of Aloe barbadensis which either display wound healing, anti-inflammatory, or both properties plus analgesic activity.

3.1 Aloe barbadensis Gel as a Beneficial Agent Against RA-Associated Symptoms

Aloe displays three main actions in rheumatoid arthritis – cell regeneration to heal wounds, anti-inflammatory and analgesic activity. In 1989, the anti-inflammatory action of Aloe barbadensis was demonstrated by Davis et al. in diabetic mice, selected because of the poor healing abilities of the animals [44]. The anti-inflammatory properties were displayed in streptozotocin-induced diabetic mice compared with the use of pure gibberellin (found in Aloe barbadensis). Similar inhibition of inflammation was observed in both experiments, highlighting Aloe barbadensis’ anti-inflammatory properties. In their next study, they used a synovium-like pouch wall by introducing air under the skin [45]. Davis’ group treated the pouch bearing mice with 1% carrageenan on day 7, to stimulate inflammation like in arthritis. The synovial pouches inflamed by 50% due to carrageenan, reduced in vascularity after treatment with 10% Aloe barbadensis. This showed anti-inflammatory activity which was boosted when mast cell numbers reduced by 48% in comparison with just 1% in mice treated with carrageenan. Increase in the number of fibroblasts also illustrated the stimulation of fibroblast growth and repair by Aloe barbadensis [45].

Yadav et al. further researched on the wound healing activity of Aloe barbadensis by topical application with experimental rats and observed a strong acceleration of the healing process [53]. As confirmed by biochemical studies, collagen synthesis improved significantly. Nandanwar et al. also used cow ghee to demonstrate Aloe barbadensis’ commendable wound healing activities [54]. As shown by Fernanda’s group, this activity was accelerated with the simultaneous application of microcurrent [55].

Egesie’s group separately investigated and found Aloe barbadensis’ strong analgesic and anti-inflammatory activities on hind paw edema induced with formalin and abdominal writhing induced with acetic acid [57]. These activities could serve as inflammatory and pain mediators through the Central Nervous System. Ghosh et al. also researched on the analgesic activity of Aloe barbadensis.

3.2. Specific Phytochemicals of Aloe barbadensis Providing Beneficial Effects in RA

3.2.1. Anthroquinones of Aloe barbadensis in RA   

Anthraquinones are potent inflammation inhibitors and are a main group of compounds in Aloe barbadensis.

Reports suggest that emodin found in Aloe barbadensis is beneficial in RA and Hwang et al demonstrated the mechanism through which this can be achieved [61]. They reported that emodin inhibits NF-kB subunits from nuclear translocation and DNA binding, related to its inhibition of cytoplasmic IkBα degradation. They also showed that emodin suppressed the differentiation of osteoclast induced by momocyte-colony stimulating factors (M-CSF) and the activation of NF-kB ligand receptors in bone marrow macrophages.

The anti-inflammatory properties of Aloe barbadensis constituents like aloe-emodin and aloin reasonably come from their polyphenolic structure. Park et al demonstrated this experimentally, using these phytochemicals against LPS-stimulated NO and prostaglandin E2 (PGE2) release in raw 264.7 macrophages [62].

Aloe-emodin and aloin possibly inhibiting inflammation by blocking iNOS and COX-2 mRNA expression was their conclusion [62].

Zhu et al used in vivo experiments to discuss the aloe-emodin action (from ginger) in arthritic mice. Arthritis induced with bovine type-II collagen immunization was developed in mice. From day 21 to 42 after immunization, they were treated aloe-emodin. Looking at the swelling of the hind paw, the disease severity was greatly reduced.

Hajhashemi et al recently evaluated Aloe gel’s (from Aloe littoralis) in vivo dual activities, as an anti-inflammatory and wound healing agent in rats [65]. They got positive results while conducting anti-inflammatory activity in rat paw edema induced with carrageenan and observing wound healing by creating burn wounds using well-established methods [66]. And they reported emodin as being vital to these activities.

3.2.2 Polysaccharides of Aloe barbadensis in RA   

Mannose-6-phosphate is an Aloe barbadensis polysaccharide claimed to serve in both anti-inflammatory and wound healing activities (Figure 3) [68]. The biological response of wound healing is usually initiated by the communication of polypeptide hormones or growth factors among cells, as they bind with cell surface receptors (fibroblast receptor). According to many different groups, insulin-like growth factor II and mannose-6-phosphate link to different binding sites of the same receptor, activating fibroblast surface receptor.

Other Aloe barbadensis polysaccharides, acemannan, and glucomannan also appear to promote wound healing and acemannan seem to work in a two-step mechanism. It first stimulates the production of fibrogenic cytokines by macrophage activation before combining with growth factors to enhance their stability, extending granulation tissue stimulation [69].

3.2.3. Aloe barbadensis enzymes in RA

Aloe barbadensis enzymes are also reported as having anti-bradykinin action.

Obata and Shelton groups showed separately that Aloe’s carboxypeptidase helped ease this pain by breaking bradykinin down [74, 75]. Bradykinase is another Aloe enzyme claimed to possess anti-inflammatory activity [70].

3.2.4. Aloe barbadensis Sterols and other Phytochemicals in RA

Davis’ group observed wound healing acceleration by Aloe barbadensis growth hormones and reported that they masked wound healing inhibitors such as sterols and some amino acids. The also showed that Aloe barbadensis sterols reduced inflammation significantly [76].

Rajeswari et al. stated that lupeol and salicylic acid in the juice of Aloe barbadensis act as analgesics…

…reported that Aloe barbadensis fatty acids, cholesterols, campesterol and β-sitosterol showed anti-inflammatory activity [70, 77]. Hutter et al. isolated a new chromone compound from Aloe barbadensis in the last decade and demonstrated its anti-inflammatory activity which was very similar to an equal dose of hydrocortisone [78].

4. CONCLUSION

Rheumatoid arthritis is affecting and incapacitating millions of people across the globe, mostly elderly people. It restricts mobility, leading to physical and mental depression in affected individuals. Currently available allopathic drugs fail to cure RA and only relieve the symptoms alongside many adverse effects. Hence, there is an urgent need for new drugs for RA treatment. With plants popular as the source of many drugs (e.g. artemisine, quinine, reserpine, vincristine, etc.), they could prove useful in finding new treatments for RA. Some of the mentioned phytochemicals found in Aloe barbadensis can actually bring relief to RA patients by enhancing wound healing, reducing inflammation and easing pain. These are all common symptoms of RA. Therefore, Aloe barbadensis and its phytochemical have massive potential for more research to develop new and more effective drugs for rheumatoid arthritis treatment.               

            

   

              

       

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