Clinical Features and Treatment of Rheumatoid Arthritis: A Review

 

Tanaji D. Nandgude¹*, Priyajit S. Hasabe¹, Anuja K. Kolsure²

¹Dr. D. Y. Patil. Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, Maharashtra, India- 411018.

²JSPM’S Jaywantrao Sawant College of Pharmacy and Research, Hadapsar, Pune, Maharashtra, India- 411028.

 

ABSTRACT:

It is evident that the morning symptoms of rheumatoid arthritis (RA) are linked to the circadian abnormal increase in night inflammation, favoured by inadequatecortical secretion under conditions of active disease. Therefore, exogenous glucocorticoids treatment is recommended in RA at low doses in cetimay partially act like a ‘replacement therapy’. The prevention/treatment of the night up regulation of the immune/ inflammatory reaction (and related flare of cytokine synthesis) has been shown to be more effective when exogenous glucocorticoids administration is obtained with a night time release formulation. Formulation large scale trials documented that modified-release prednisone has greater efficacy then morning prednisone for long term low dose glucocorticoids treatment in patients with RA, showing at least a more significant reduction in morning joint stiffness. Interestingly, despite a considerably higher cost than conventional prednisone, chronotherapy with night time release prednisone was recognised as a cost effective option for patients with RA not on glucocorticoids who are eligible for therapy with biological disease modifying antirheumatic drug (DMARDs). Moreover, since different cell populations involved in the inflammatory process are particularly activated during the night, other therapeutically approaches used in RA, for example, conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs), should follow the same concepts of glucocorticoids chronotherapy. Indeed, bedtime methotrexate chronotherapywas found to improve RA symptoms compared to the current standard dosing methods, and several available NSAIDs (i.e., indomethacin, aceclofenac, ketoprofen, flurbiporfen, lornoxicam) have been very recently modified in their formulation, in order to obtain chronotherapeutical effects inRA.

 

 

 

INTRODUCTION:

Rheumatoid arthritis (RA) vary within a day and between days, and the morning joint stiffness observed in almost all patients with active RA is also considered one of the most peculiar diagnostic criteria of the disease. Similarly, other RA symptoms, such as joint pain and functional disability, arecommonly most severe in the early morning by following 24 h cycles, and are a consequence of altered neuroendocrine and immune/ inflammatoryactivities.¹

 

Therefore, it is not surprising that also in other chronic inflammatory rheumatic disease including polymyalgia rheumatic (PMR) and ankylosing spondylitis, symptoms of pain and stiffness typically are most prominent during the early morning, similar to RA. RA is a progressive inflammatory autoimmune disease with articular and systemic effects.² Its exact cause is unknown, but genetic and environmental factors are contributory. T cells, B cells and the orchestrated interaction of pro-inflammatory cytokines play key roles in the pathophysiology of RA. Differentiation of naive T cells into Th 17 (TH17) cells results in the production of IL-17, a potent cytokine that promotes synovitis. B cells further the pathogenic process through antigen presentation and autoantibody and cytokine production. Joint damage begins at the synovial membrane, where the influx and/or local activation of mononuclear cells and the formation of new blood vessels cause synovitis. Pannus, the osteoclast-rich portion of the synovial membrane, destroys bone, whereas enzymes secreted by synoviocytes and chondrocytes degrade cartilage.^3-5 It is now evident that the morning symptoms, at least in RA, are linked to the circadian increase in pro inflammatory cytokines, as a result of an increased night inflammation. Indeed, cytokines, such as tumour necrosis factor (TNF) α and interleukin (IL) 6, are highly increased in patients with active RA in the very late night hours, whereas they are present at very low levels afternoon. Following several signalling, it is now evident that neuroendocrine circadian rhythms play an important role in RA clinical symptomatology. Pro inflammatory night hormones, such as melatonin (and prolactin), which follow a 24 h daily cycle, as well as the full availability of bioenergies during the night, are recognized among the triggers/enhancers for increased release and serum concentrations of cytokines (figure 1).^6-8.

 

 

Figure 1 Circadian sequence of nocturnal hormone secretion that induces activation (melatonin, prolactin) and/or dowregulation (cortical) of the immune inflammatory response during the night. Clinical consequences of altered hormonal balance in rheumatoid arthritis (RA) include morning symptoms such as joint stiffness and pain

 

The circadian clock and RA^9-11:

In all individuals, a circadian clock drives daily rhythms in physiology necessary to synchronize the human functions with the 24 h environment. Therefore, physiological functions under circadian control include the sleep-wake cycle, heart rate, blood pressure, body temperature, as well as endocrine gland regulation (i.e., gonadal and adrenal steroid genesis) and immune response. These daily rhythms are con- trolled by a central pacemaker, who is found in a hypothalamic region located above the optic chiasm called the suprachiasmatic nucleus (SCN) The SCN collects from the eyes the light inputs via the retinohypothalamic tract. The central pacemaker synchronises additional peripheral oscillators found locally within organs, tissues and cells.¹⁰ These peripheral clocks are synchronized by these peripheral clocks are synchronized by the central clock, but are self-sustain and but are self-sustaining and can be entrained by external cusec has temperature. A bidirectional interaction between inflammation and the circadian clock has been shown recently, anddisruption of the clock has a significant effect on the performance of the immune system, with a possible impact on the pathogenesis of RA. Conversely, inflammation can directly alter cellular expression of core clockgenes. Once again, the endocrine system mediates the dissemination of timing signals from the SCN throughout the body and to the immune system, and two night hormones act as circadian agent’s glucocorticoids and melatonin (prolactin). Both are important in regulation of the immune/inflammatory response, and contribute to the pathogenesis of RA figure: 2¹²

 

 

Fig 2: The daily neurimmuno endocrine rhythms (gonadal, adrenal, pituitary hormones) are controlled by a central pacemaker, which is found in a hypothalamic region called the suprachiasmatic nucleus (SCN) of the centralnervous system (CNS). APC, antigen presenting cell; DHEA, dehydroepiandrosterone; TheT helper cell; T regulatory T cell.

 

Symptoms of rheumatoid arthritis (RA) frequently show diurnal variation, with exacerbations in the morning (Figure3). This variation in disease expression is accompanied by daily oscillations in circulating concentrations of disease-mediating cytokines [2]. In particular IL-6 shows robustoscollations and punctuation sin serum IL-6 levels correlate with changes in disease symptoms. This review summarises the evidence for a primary role for the circadian clock in the observed diurnal variations in disease activity, and its role in further aspects of RA disease manifestation. We consider how this information can be utilised, not only tomodify existing treatment regimens, but to develop new therapeutic strategies to treatRA.¹³

 

Figure 3: Rheumatoid arthritis shows diurnal variation in disease symptoms and markers.

What is rheumatoid arthritis?¹⁴

Rheumatoid arthritis is an autoimmune disease that causes inflammation in your joints. To understand how rheumatoid arthritis develops, it helps to understand how a normal joint works first.

 

What is the outlook?¹⁵

Because rheumatoid arthritis can affect different people in different ways, we can’t predict how the condition might develop for you. However, a study of a large group of people with rheumatoid arthritis gave us some general guidelines (see Figure 4): Possibly as many as 1 in 5 people with rheumatoid arthritis always have very mild symptoms that cause few problems. They may have little ornodamage to their joints, or have only very mild damage to a few joints. Most people with rheumatoid arthritis have some damage to a few joints. Only about 1 in 20 of those with rheumatoid arthritis has quite severe damage to a lot of theirjoints. The condition may become increasingly worse, often quite quickly. These people tend to have inflammation in other parts of their body besides their joints. Blood tests and x-rays will help your doctor assess how fast your arthritis is developing and what the outlook for the future may be. This will also help your doctor to decide which form of treatment torecommend. Most people can have periods of months or even years between flare ups, when there’s little inflammation, although damage can still be caused in these periods. However, most people, especially if they get the right treatment, will have relatively few symptoms and will be ableto lead full lives. The outlook for people with rheumatoid arthritis isimproving all the time as new and more effective treatments become available.

 

Fig 4:How people with rheumatoid arthritis are likely to be affected

 

How does a normal joint work?¹⁶

A joint is where two bones meet. Most of our joints are designed to allow the bones to move in certain directions and within certain limits. For example, the knee is the largest joint in the body and one of the most complicated. It must be strong enough to take our weight and must lock into position so we can stand upright, but it also has to act as a hinge so we can walk. It needs to withstand extreme stresses, twists and turns, such as when we run or play sports. Figure 1 shows a normal joint. The end of each bone is covered with cartilage that has a very smooth, slippery surface. The cartilage allows the ends of the bones to move against each other almost without friction. The joint is surrounded by a membrane (the synovium) that produces a small amount of thick fluid (synovial fluid) which nourishes the cartilage and lubricates the joint. The synovium has a tough outer layer called the capsule that, together with the ligaments, holds the joint in place and stops the bones moving too far. Strong, fibrous bands or cords called tendons anchor the musclesto the bones.

 

What happens in a joint affected by rheumatoid arthritis?^17-19

Figure 6 shows the changes in a joint affected by rheumatoid arthritis. Inflammation takes place within the synovium. The result is very similar to inflammation that you may have seen if you’ ve had an infected cut or wound it goes red, swells, produces extra fluid and hurts. The redness is caused by the flow of blood increasing. As a result, the inflamed joint may feel warmer than usual. The inflammation is caused by a build-up of fluid and cells in the synovium. The joint hurts for two reasons: Nerve endings are irritated by the chemicals produced by the inflammation. The capsule is stretched by the swelling in the joint. When the inflammation goes down, the capsule remains stretched andcan’t hold the joint in its proper position. This can cause the joint to become unstable and it can move into unusual or deformed positions. Some damage is done to the joints every time they’re inflamed, and the joint can be worn away after repeated flare-ups (periods where your joints become inflamed and painful, sometimes known asflares).

 

Fig 6: A joint affected by rheumatoidarthritis

 

Fig5: A normal joint

 

Differences in Certain Types of Arthritis²⁰:

What Are Some of the Differences Between RA and Other Common Types of Arthritis?

Most people are familiar with the term arthritis. But many people may mistake RA for certain other types of arthritis. Even though the symptoms may seem the same, the diseases are quite different. Getting an appropriate treatment plan for RA depends on getting an accurate diagnosis as early as possible. Only a doctor can determine whether you have RA or another type of arthritis.

Table 1: Differences in Certain Types of Arthritis:^21-25.

	Rheumatoid Arthritis	Osteoarthritis	Psoriatic Arthritis	Ankylosing Spondylitis
Type of Disease	Autoimmune arthritis	Known as the “wear and tear” type of arthritis and is associated with factors such as aging, injury, or obesity	A type of autoimmune arthritis associated with psoriasis (a disease that causes red, scaly patches on the skin)	A type of autoimmune arthritis that mostly affects the back and hips
Symptoms	Joint pain, swelling, and stiffness; decreased range of motion; fever, fatigue, and loss of energy can also occur	Joint stiffness, pain, and decreased range of motion	Joint pain, swelling, and stiffness, as well as tenderness or pain where tendons or ligaments attach to bones. Red, scaly patches of skin often on the elbows, knees, and scalp	Low back pain and stiffness, as well as tenderness or pain where tendons or ligaments attach to bones
Location of Symptoms	Often causes swelling in pairs of joints—especially smaller ones (both hands, both ankles, etc.)	Usually affects weight-bearing joints (ie, back, hip, knee) as well as the neck, small finger joints, and big toe	Usually affects the ankles, knees, fingers, toes, and lower back	Mostly affects the joints of the spine and also where the spine attaches to the hips
Time of Day	Generally worse in the morning or after long rest and lack of activity	Tends to get worse with activity throughout the day	Tends to be worse in the morning or after a period of rest	Usually worse after a period of rest or after waking in the morning and may also improve with exercise
Age of Onset	Usually occurs between 30 and 60 years of age, though can occur at any age	Most commonly affects middle-aged and older people	Usually occurs between 30 and 55 years of age. Skin symptoms often appear first	Most often begins from the late teens to 35 years
Prevalence	Approximately 1.3 million people have RA in the US	An estimated 27 million people have osteoarthritis in the US	Between 6% and 42% of all people in the US with psoriasis have psoriatic arthritis	An estimated 0.2% of people in the US have ankylosing spondylitis

 

Genetic Factor:

Psoriasis and PSA are strongly heritable conditions2, 3 when compared with other inflammatory rheumatic conditions. Family history of psoriasis / PSA (or other features of the SPA spectrum such as inflammatory bowel disease and iritis) can provide strong support for the diagnosis of PSA when assessing a patient suspected of having the disease. 3 PSA is thought to be more heritable than psoriasis. 1 Different human leukocyte antigen alleles are associated with PSA.1 Certain gene polymorphisms are also more strongly associated with PSA, including tumour necrosis factor alpha (TNF-α) promoter, major histocompatibility complex class 1, and some interleukin (IL) receptors. The pattern of inheritance is complex and multigenic and varies from dominant in some families to recessive in others.

 

Symptoms of rheumatoid arthritis²⁷.

Common symptoms of rheumatoid arthritis include:

·      Joint pain andswelling

·      Stiffness

·      Fatigue, depression and irritability

·      Anemia

·      Flu like symptoms, such as feeling generally ill, feeling hot andsweating.

·      Less common symptoms include:

·      Weightless

·      Inflammation in the eyes

·      Rheumatoid nodules

·      Inflammation of other parts of thebody.

 

PATHOPHYSIOLOGY^28-29:

It is still not clear what exact mechanism lies behind the development of PSA. It is thought to be multifactorial and secondary to environmental, genetic, and immunological factors.1 Over-activation of the immune system when triggered in the skin and joints causes an inflammatory cascade, resulting in signs such as scaly skin plaques and joint synovitis in those individuals who are genetically susceptible. The synovitis which is detected in PSA can be pathologically different to that found in rheumatoid arthritis (RA). 3 In PSA the synovitisresembles more of a SPA type, with high numbers of neutrophils and greater vascularity when compared with the RA synovitis, thus suggesting that PSA is a separate condition from RA both genetically and pathologically. Bone changes in PSA are thought to be secondary to osteoclast proliferation which is activated by cytokines. These changes include erosions, osteolysis, and new bone formation.1 Inflammation in PSA can also affect surrounding tissue such as ligaments and tendons, which is more uncommon in RA. Inflammatory cells infiltrate the ethereal and ligament tissues causing subsequent pain and swelling. Imaging studies have shown that joint capsules and ten synovial tissues can also be affected by inflammation in PSA. Thus in clinical assessment, it is important to focus on other sites of inflammation and not just concentrate on how many tender or swollen joints the patient has.Pro-inflammatory cytokines such as TNF-α are present in psoriatic plaques and synovial fluid in large amounts.¹ TNF-α is also found in many other arthropathies and biologic drugs which are aimed at blocking TNF-α have been effective therapies for such conditions. Although they are useful in PSA, other therapies such as the B cell-depleting rituximab is not as effective in PSA when compared with RA.³ Thus there are still distinct cell lines that are unique to the inflammation found in PSA and which need further research for therapeutic purposes. In particular, T helper cell 17, IL-17, and IL-23 are inflammatory mediators which.

 

Therapy³⁰:

Nonsteroidal anti-inflammatory drugs (NSAIDs) help with symptomatic relief, but they do not alter the disease course or prevent disease progression. Intra-articular steroid injectionscan be used for symptomatic relief. In psoriatic arthritis, dramatic flares in skin disease have been reported with corticosteroid taper; therefore, systemic corticosteroids ideally should be avoided in this patient population. Physical therapy may also be helpful in symptomatic relief. Diseases modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment for patients suffering from PsA. Traditional oral agents include methotrexate, sulfasalazine, cyclosporine and leflunomide. The TNF-α inhibitors include etanercept, infliximab, adalimumab, and golimumab. Currently, the most effective class of therapeutic agents for treating PsA is the TNF-α inhibitors; however, these drugs show a 30 to 40% primary failure rate in both randomized clinical trials and registry-based longitudinal studies.

 

CLASSIFICATION OF ANTIRHEUMATIC DRUGS^31-33:

1. Symptom-modifying antirheumatic drugs

(S-MARDs)

These drugs improve the symptoms and clinical features of inflammatory synovitis.

 

a. Nonsteroidal anti-inflammatory drugs (NSAIDs):

Eg: Clinoril (sulindac)

Daypro (oxaprozin)

Feldene (piroxicam)

Indocin (indomethacin)

Lodine (etodolac)

 

b. Corticosteroids:

e.g.: Bethamethasone, (Celestone)

Prednisone (Prednisone Intensol)

Prednisolone (Orapred, Prelone)

Triamcinolone (Aristospan Intra Articular, Aristospan Intraregional, Kenalog)

Methylprednisolone (Medrol, Depo-Medrol, SoluMedrol)

 

c. Others, e.g., antimalarials, gold, D-penicillamine, antimetabolites, immunomodulators,‖

etc. (sometimes known as SAARDs)

 

2. Disease-modifying antirheumatic drugs (D-MARDs)³⁴:

Table 2 : Disease-modifying antirheumatic drugs

Commonly used drugs	Less commonly used drugs
Methotrexate	Chloroquine
Hydroxychloroquine	Gold(parenteral and oral)
Sulphasalazine	CyclosporineA
Leflunomide	D-penicillamine/bucillamine

 

Table 3: Clinical information about DMARDs^36-39

NAME	DOSE	SIDE EFFECTS	MONITORING	ONSET OF ACTION
Hydroxycloroquine	200mg twice daily x 3 months, then once daily	Skin pigmentation, retinopathy, nausea, psychosis, myopathy	Fundoscopy and perimetry yearly	2-4 months
Methotrexate	7.5-25 mg once a week orally/c or i/m	GI upset, hepatotoxicity, Bone marrowsuppression, pulmonary fibrosis	Blood counts, LFT 6-8 weekly, Chestx-ray annually, urea / creatinine 3 monthly; Liver biopsy	1-2 months
Sulphasalazine	2gm daily p.o	Rash, myelosuppression, may reduce sperm count	Blood counts ,LFT 6-8 weekly	1-2 months
Leflunomide	Loading 100 mg daily x 3 days, then 10-20 mg daily p.o	Nausea,diarrhoea,alopecia, hepatotoxicity	LFT 6-8 weekly	1-2 months

 

These modify the course of rheumatoid arthritis, as demonstrated by either or both:

a.    Prevention or decreased rate of progression of joint erosions

b.    Sustained improvement in function associated with decreased inflammatory synovitis.

3. Surgical Approaches^40-41:

Synovectomy is ordinarily not recommended for patients with rheumatoid arthritis, primarily because relief is only transient. However, an exception is synovectomy of the wrist, which is recommended if intense synovitis is persistent despite medical treatment over 6 to 12 months. Persistent synovitis involving the dorsal compartments of the wrist can lead to extensor tendon sheath rupture resulting in severe disability of hand function. Total joint arthroplasties, particularly of the knee, hip, wrist, and elbow, are highly successful. Other operations include release of nerve entrapments (e.g., carpal tunnel syndrome), arthroscopic procedures, and, occasionally, removal of a symptomatic rheumatoid nodule.

 

CONCLUSIONS:

In patients with RA, the stiffness and functional joint disability characterizing the early morning hours are related to the night activation of the immune / inflammatory response. The prevention/treatment of the up regulation of immune cell activity (and related are of cytokine synthesis) has been shown to be more effective when exogenous glucocorticoids availability is obtained at night-time. The positive results obtained in RA with modified release prednisone low-dose chronotherapy, following the chronobiology of the disease, seem applicable in RA even for other agents such as conventional DMARDs and NSAIDs.

 

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Accepted on 20.07.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(12): 5701-5706.