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New Therapies provide Hope for Rheumatoid Arthritis Sufferers

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Rheumatoid Arthritis causes pain, deformity, and joint damage

Rheumatoid arthritis (RA) is the most common type of inflammatory arthritis and is characterized by inflammation involving multiple joints. It affects about 1% of people worldwide, most commonly women, smokers, and people with a genetic predisposition. Besides the joints, rheumatoid arthritis may affect the skin, eyes, lungs, and may accelerate cardiovascular disease.

It is considered an autoimmune disease due to the expression of autoantibodies, specifically rheumatoid factor (RF) and antibodies to citrullinated proteins (ACPAs). If not treated appropriately, rheumatoid arthritis can cause permanent pain, disability, physical deformity, rheumatoid vasculitis, or permanent damage of joints requiring arthroplasty. For better outcomes, early diagnosis and treatment are advised.

Therapy for rheumatoid arthritis has advanced over the years, even improving the condition of some patients to the point of remission. However, many challenges persist and there is still no definitive cure for RA. Currently, treatments primarily aim to manage pain and to prevent further joint damage and disease progression.

The typical presentation of rheumatoid arthritis includes stiffness and pain of multiple joints, commonly the proximal interphalangeal, metacarpophalangeal, and wrist joints. Patients present with morning stiffness lasting longer than half an hour and may also display systemic symptoms like fever, fatigue, anemia, and weight loss.

Rheumatoid nodules, firm lumps beneath the skin, and mild synovial thickening may be observed upon physical examination. Rheumatoid arthritis patients may also present with extra-articular manifestations such as pleural effusion, keratoconjunctivitis sicca, pulmonary nodules, interstitial lung disease, and episcleritis.

RA Diagnosis

Rheumatoid arthritis should be suspected in the case of unexplained swelling of more than one joint. RA must be differentiated from other etiology by history taking and thorough physical examination. Positive serology testing for rheumatoid factor, anti-citrullinated protein, elevated inflammatory markers, and elevated erythrocyte sedimentation rate is diagnostic for rheumatoid arthritis.

Rheumatoid arthritis can easily be clinically differentiated from osteoarthritis (OA), the most common type of arthritis. OA typically involves the distal interphalangeal joints while RA often affects the metacarpophalangeal and proximal interphalangeal joints.

Osteoarthritis is not autoimmune and is caused by wear and tear of joints. It has no extra-articular effects and characteristically involves only one side of the body while rheumatoid arthritis is symmetrical in nature. Additionally, people with OA often experience relief from morning stiffness within half an hour as opposed to a longer duration of stiffness in RA patients.

Management of Rheumatoid Arthritis

The aim of rheumatoid arthritis treatment is to manage pain, reduce inflammation, improve joint function, and prevent joint deformity. Treatment is customized to patient needs and may involve combining pharmacotherapy, exercise, rest, and patient education. 1st-line therapy targets pain-relief and reducing joint inflammation. Medications of choice include NSAIDS (nonsteroidal anti-inflammatory drugs) such as Aspirin, Ibuprofen, Naproxen, and Etodolac.

The aim of 2nd-line management is to prevent the progression of joint damage and deformity and includes disease-modifying antirheumatic drugs (DMARDS). The typical 1st-choice drug (the anchor drug) is Methotrexate (MTX). However, due to its hepatotoxic potential, methotrexate is not appropriate for patients with liver disease or frequent alcohol consumption. Other disease-modifying antirheumatic drugs should be prescribed if the disease persists. These include hydroxychloroquine, sulfasalazine, and leflunomide.

Despite the availability of many DMARDs, many patients are unsuccessful in attaining or maintaining remission and may progress to develop irreversible joint damage and disability. If patients display signs of disease progression, glucocorticoids may be added at low dosages to the treatment regimen. Corticosteroids are associated with many adverse effects like rapid bone loss leading to fractures and osteoporosis, so their use is limited to more refractory cases.

Slightly newer medications are TNF inhibitors like etanercept, adalimumab, certolizumab pegol, infliximab, and golimumab. TNF inhibitors relieve symptoms by preventing the recruitment of inflammatory cells and are prescribed if 2nd-line drugs (DMARDS) are ineffective. Other drugs that may be used for rheumatoid arthritis include anakinra, rituximab, tocilizumab, and tofacitinib. These drugs interact with inflammatory cytokines or immune cells to relieve joint inflammation.

Newer Therapies for Rheumatoid Arthritis

A new investigational therapy for rheumatoid arthritis is the usage of repository corticotropin injection (RCI or Acthar gel). It consists of a mix of adrenocorticotropic hormone analogues along with other pituitary peptides. It acts agonistically with all five of the melanocortin receptors (MCRs) and has different mechanisms that may potentially explain its therapeutic activity in rheumatoid arthritis.

RCI (Acthar gel) for the treatment of rheumatoid arthritis is currently under clinical trial in the United States and results of preclinical studies demonstrate that it activates different nonsteroidogenic pathways that may regulate immunity and inflammation. Melanocortin receptors are expressed by multiple immune cells which supports the suggestion that MCRs have additional roles in inflammation. So far, studies have shown that bone turnover markers remain stable upon Acthar gel or RCI therapy demonstrating that bone loss is not a potential side effect. Additionally, no other significant adverse effects have been recorded by previous studies.

Another potential therapy is ultrasound stimulation of the spleen. Rehabilitation specialists often use ultrasound of the joints as a complementary therapy for symptomatic rheumatoid arthritis. Currently, the usage of US stimulation of the spleen in rheumatoid arthritis is under clinical trial in the United States. The mechanism proposed is that the parasympathetic vagus nerve sends signals to the splenic nerve in response to injury or infection, interacting with splenic immune cells. Experiments demonstrate that when the vagus nerve is stimulated with a current (invasively or by US), immune response is depressed as a result of this neural-immune reflex.

 
Resources:
  1. Wasserman A. Rheumatoid Arthritis: Common Questions About Diagnosis and Management. Am Fam Physician. 2018;97(7):455-462.
  2. Pisetsky DS. Advances in the Treatment of Rheumatoid Arthritis: Costs and Challenges. N C Med J. 2017;78(5):337-340. doi:10.18043/ncm.78.5.337
  3. Bullock J, Rizvi SAA, Saleh AM, et al. Rheumatoid Arthritis: A Brief Overview of the Treatment. Med Princ Pract. 2018;27(6):501-507. doi:10.1159/000493390
  4. Fleischmann R, Furst DE, Connolly-Strong E, Liu J, Zhu J, Brasington R. Repository Corticotropin Injection for Active Rheumatoid Arthritis Despite Aggressive Treatment: A Randomized Controlled Withdrawal Trial. Rheumatol Ther. 2020;7(2):327-344. doi:10.1007/s40744-020-00199-3
  5. Zachs DP, Offutt SJ, Graham RS, et al. Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis. Nat Commun. 2019;10(1):951. Published 2019 Mar 12. doi:10.1038/s41467-019-08721-0



     

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