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Seronegative Arthritis

Seronegative rheumatoid arthritis is a subtype of rheumatoid arthritis that is not accompanied by the presence of a positive rheumatoid factor in the laboratory tests.


Presentation

Ankylosing spondylitis most commonly affects the axial skeleton and less frequently the peripheral joints, shoulders or hips. It is characterized by chronicity, and is first diagnosed in the ages of early adulthood (20 to 30 years old). Pain and stiffness of the spine are the predominant symptoms and as the condition progresses, the spinal skeleton is fused into a hyperkyphotic posture. The eyes might also be affected by the condition and develop uveitis, although it is not a common complication.

Reactive arthritis usually affects the joints, eyes and urethra. Symptomatology related to the subsequent arthritis, conjunctivitis and urethritis is anticipated within 1 to 4 weeks after the infection, although there have been some reported cases of it starting within years after a GI or GU infection.

Patients primarily complain about arthritic pains, since the conjunctivitis and urethritis usually produce mild symptoms [9] [10]. Urethritis, an inflammation of the urethra, may present with penile discharge, dysuria or hematuria in men. In women, it may be suspected when the patient complains of dyspareunia or cervical inflammation. Asymptomatic urethritis is not uncommon [11].

Conjunctivitis most commonly accompanies reactive arthritis following salmonellosis or shigellosis [11]. This medical entity, alongside uveitis, which is also common, produce symptomatology such as ophthalmic pain and discharge, red eyes and a distorted vision. Uveitis is also frequently observed in individuals affected by reactive arthritis and is typically unilateral.

Arthritis is also a major symptom. It can affect the knees and ankles as a more frequent site, and secondarily the wrists or fingers etc. Entheses are prone to inflammation as well [11], observed in up to 1/5 of the individuals diagnosed with reactive arthritis. The predominant symptoms are Achilles tendonitis and pain induced by the insertion of the kneecap into the tibia. Vertebral arthritis is also a possibility, alongside sacroiliitis.

Weight Gain
  • I hope it works I am worried about the posts about weight gain. I eat very clean and exercise 6 days a week. I also work with pre-schoolers so that worries me too. If anyone can...[dailystrength.org]
Camping
  • Your rheumy seems on top of it, going ahead with treatment even though not absolutely positive you're in the RA camp. depotblue 04/28/2014 yep welcome. glad you are here. sorry you have the beast. standard operating procedure for your treatment and in[dailystrength.org]
Arthritis
  • Seronegative rheumatoid arthritis is a type of rheumatoid arthritis.[symptoma.com]
  • Abstract Behcet's disease (BD) with arthritis is often confused with seronegative arthritis (SNA) because of shared clinical symptoms and the lack of definitive biomarkers for BD.[ncbi.nlm.nih.gov]
  • Abstract The term seronegative arthritis (alternately labelled seronegative spondarthritis or spondyloarthritis) includes ankylosing spondylitis; Reiter's syndrome; psoriatic arthritis; enteropathic arthritis; and some forms of juvenile chronic arthritis[ncbi.nlm.nih.gov]
  • The diseases described are spondyloarthritides (SpA), including ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), inflammatory bowel disease-related arthritis (IBDa), enthesitis-related arthritis (ERA) of the paediatric[ncbi.nlm.nih.gov]
  • OBJECTIVE: To determine whether long term doxycycline improves symptoms in patients with chronic seronegative or reactive arthritis.[ncbi.nlm.nih.gov]
Joint Swelling
  • swelling, tenderness or pain, and sometimes redness.[everydayhealth.com]
  • Some of the most important symptoms in diagnosing seronegative rheumatoid arthritis include: Joint pain, stiffness specifically in the hands but also in knees, elbows, hips, feet and ankles Joint swelling and redness Joint tenderness Symmetrical symptoms[rheumatoidarthritis.org]
  • The Ottawa Panel partially agrees with the Canadian Arthritis Society, which views TENS as beneficial for pain and joint swelling in patients with RA. The American Pain Society gives TENS a fair recommendation for pain relief for RA patients.[everydayhealth.com]
  • It can include redness, joint swelling and pain, often in knees , ankles , and feet. Psoriatic arthritis affects major joints of the body, as well as the fingers and toes, along with the back and pelvis.[webmd.com]
Type A Personality
  • I am the type of person who doesn't typically question the doctor or dares to ask a lot of questions.[dailystrength.org]
Dyspareunia
  • In women, it may be suspected when the patient complains of dyspareunia or cervical inflammation. Asymptomatic urethritis is not uncommon. Conjunctivitis most commonly accompanies reactive arthritis following salmonellosis or shigellosis.[symptoma.com]
Hyperactivity
  • There were two markers identified, elevated methionine sulfoxide and citrulline, that were associated with increased oxidative stress, providing a potential link to BD-associated neutrophil hyperactivity.[ncbi.nlm.nih.gov]
Neglect
  • […] with acute infection, atypical pneumonia and flu-like symptoms, endocarditis, osteoarticular manifestations and severe disease are possible, especially when the patient has a suppressed immune system; however, these severe complications are typically neglected[ncbi.nlm.nih.gov]

Workup

The first step toward diagnosing ankylosing spondylitis is a thorough medical history. A compatible medical history involves an age of onset before the age of 45 years old, pain that has been experienced for more than three months, pain that deteriorates when the individual remains immobile and improvement of the symptoms with the use of non-steroidal anti-inflammatory drugs. Other possible indicators of ankylosing spondylitis are a prior history of uveal tract or iris inflammation, or a medical history involving autoimmune inflammatory bowel diseases, such as ulcerative colitis

The physical examination is expected to reveal regions of inflammation, involving the spine, sacroiliac joint, the heels and thorax. Spinal mobility should also be assessed.

As far as imaging modalities are concerned, a definitive diagnosis of ankylosing spondylitis is established when the involvement of the sacroiliac joint is confirmed via a radiograph or a magnetic resonance imaging scan. The process entails various difficulties, such as the fact that erosions are detectable in an x-ray after nearly 10 years of the onset and the absence of a valid interpretation protocol concerning the MRI findings.

As far as the HLA-B27 gene is concerned, its identification cannot be used as a screening method to determine future ankylosing spondylitis patients. It is, however, expected, that amongst some ethnicities (Caucasian individuals and people from the Mediterranean), a vast majority of ankylosing spondylitis patients are positive for the HLA-B27 gene. Additional tests may be able to confirm the presence of inflammation, as indicated by the detection of an augmented ESR or c-reactive protein (CRP), although these findings are indeed non-specific and may not be present in all patients.  

With regard to reactive arthritis, the condition is clinically diagnosed in the majority of the cases, with no particular diagnostic guidelines available [12]. The presence of a prior infection, accompanied by symptoms of arthritis usually suffice to raise suspicion. Various tests can be carried out to confirm the infection.

Coxiella Burnetii
  • Abstract Coxiella burnetii is the agent of Q fever , an emergent worldwide zoonosis of wide clinical spectrum.[ncbi.nlm.nih.gov]
HLA-DR1
  • In contrast to the results in a group of 30 RF-positive RA patients, the percentage of patients having at least one of the susceptibility alleles (HLA DR1 or HLA-DR4) was not significantly higher in patients with RF-negative, ANA-positive arthritis than[ncbi.nlm.nih.gov]

Treatment

The treatment for ankylosing spondylitis does not aim at curing the condition, but at the alleviation of the pain and predominant symptomatology. The first step involves the administration of non-steroidal anti-inflammatory agents, such as naproxen and indomethacin in order to reduce the existing inflammation and pain. Should the patient exhibit no response to these medications, anti-TNF medications can secondarily be applied, such as infliximab, adalimumab or etanercept. These drugs can be administered either IV or IM.

The reduction of inflammation alongside physical therapy can greatly contribute to the delay of the spine's hyperkyphotic posture. Physical therapy is capable of extending a patient's spinal extendibility and maintaining a normal posture. As a last resort, patients with a severe type of ankylosing spondylitis may be in need of surgical intervention in order to replace an irreversibly damaged joint. 

With regard to the treatment of reactive arthritis, on the other hand, the condition is self-limited. There is no treatment available to cure it earlier and the only therapeutic options aim at the management of infections and the improvement of symptoms.

Non-steroidal anti-inflammatory drugs can be prescribed for this case, alongside corticosteroids, should the NSAIDs be met with a poor response. Disease modifying antirheumatic drugs (DMARDs) are also an option, if the disease is resistant to the aforementioned types of more conventional treatment.

Similar to patients with ankylosing spondylitis, individuals suffering from reactive arthritis benefit from physical therapy as well.

Prognosis

Patients with ankylosing spondylitis have a good prognosis, unless certain factors are implicated. Bad prognostic characteristics of the disease are an early onset, an increased ESR, affected joints of the periphery and no response to the prescribed anti-inflammatory drugs.

On the other hand, reactive arthritis follows a less persistent course and is usually self-limited, after 3 to 12 months. The patients are unlikely to succumb to causes induced by the disease itself, but potential death has been associated with side effects from treatment agents. It is generally accepted that reactive arthritis resulting from a gastrointestinal infection have a better prognosis that cases that are induced by a venereal infection.

Etiology

Since seronegative arthritis is an extremely broad term, comprising various types of arthritides, each condition may be quite distinct in terms of etiology. Two of the most frequently observed types of seronegative arthritis are ankylosing spondylitis and reactive arthritis.

As far as the etiology is concerned, ankylosing spondylitis is attributed to unknown causes. It is believed to be caused by environmental and genetic factors [3].

Reactive arthritis,on the other hand, classified under the category of inflammatory arthritis, can be induced by various causes. It is often observed as a result of infection, either in the gastrointestinal or genitourinary tract, by gram negative bacteria [4]. Genetic factors are also responsible for the development of reactive arthritis in some cases. An increased prevalence amongst members of the same family has been observed and HLA-B27 has been detected in 4/5 of the patients affected by the condition [5].

Epidemiology

A far as ankylosing spondylitis is concerned, it is observed amongst individuals belonging to the Caucasian ethnic group at a rate of 0.15%- 1.8%. Patients who test positive for HLA-B27 are more frequently affected by the disease, when compared to those who test negative [6]. Psoriatic arthritis,on the other hand shows an immensely increased frequency amongst patients already affected by psoriasis, which can reach up to 42% [6]. In the population that does not suffer from psoriasis, the incidence of psoriatic arthritis is very low (0.02%-0.2%). Lastly, reactive arthritis displays a prevalence of approximately 35 per 100,000. Individuals affected by inflammatory bowel disease simultaneously frequently suffer from seronegative spondyloarthritis, at a rate of 50%.

Sex distribution
Age distribution

Pathophysiology

Similarly to what has been described before, the vast variety of the conditions belonging to the seronegative arthritis category renders the description of a unified pathophysiologic study impossible. The following mechanisms refer to two of the most common representatives of the group. ankylosing spondylitis and reactive arthritis.

Concerning ankylosing spondylitis, it is a persistent inflammatory type of arthritis, primarily affecting the sacroiliac joint. Peripheral arthritis and organs such as the skin and eyes are less frequently involved in the clinical picture.  From a pathophysiological point of view, ankylosing spondylitis is characterized by infiltration of CD4+ and CD8+ T lymphocytes, macrophages, transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α) and various other cytokines. Enthesitis is always present at the affected sites and involves the presence of granulomas in the ligaments and capsular attachment sites of the skeleton [7]. As the disease progresses, regions with enthesitis exhibit a considerable degree of fibrosis and ossificated tissue.

As far as reactive arthritis is concerned, the pathophysiological mechanism usually involves the initiation of the process by an infection, typically a gastrointestinal or genitourinary one. it is generally believed that an asymptomatic infection of the genitourinary tract entails a greater risk of complication with reactive arthritis than a fully developed infection of the gastrointestinal tract that also produces clinical symptomatology. A small but considerable percentage of patients presenting with reactive arthritis had not been previously diagnosed with any type of infection.

The primary pathophysiological mechanism involved in the pathogenesis of reactive arthritis includes HLA-B27, which is involved in the presentation of antigens to the T lymphocytes. Up to 96% of the patients affected by this type of arthritis are found to be positive for HLA-B27 and those who have a family history of the disease are more likely to develop a persistent and severe type [8]. Despite the detection of the HLA-B27 culprit and the disease's association with infection, the exact pathogenetic mechanisms have yet to be discovered.

Prevention

There is no specific measure in order to prevent any type of seronegative rheumatoid arthritis. General measures include physical exercise, taking care of one's health in general and avoiding joint injuries.

Summary

Seronegative arthritis is a group of conditions, including various subtypes of disease, which vary in terms of symptomatology, location and other clinical features. The characteristic that is shared by all the conditions is the absence of rheumatoid factor in the results of laboratory tests. The broader categorization of seronegative rheumatoid arthritis involves two categories, the inflammatory and non-inflammatory arthritis.

Rheumatoid arthritis is the most common type of inflammatory arthritis. The arthritides belonging in this category have several distinct features, such as morning stiffness which lasts for more than half an hour, an increased ESR and CRP and pain in the affected joint which is less when the patient starts to move the joint. Also, depending on the number of the joints involved, inflammatory arthritis is further divided into three other categories: monoarthritis (one joint affected), oligoarthritis (2-4 affected joints) and polyarthritis (more than 5 joints affected). On the other hand, non-inflammatory arthritis is a group of arthritides which are not accompanied by inflammation, such as osteoarthritis. These conditions are characterized by pain which deteriorates when the patient moves the joint, morning stiffness that lasts for less than half an hour and a regular acute phase response.

The characteristic of seronegativity may, in some cases, be temporary. However, a distinct group of arthritides are known to be always characterized by seronegativity, even though the conditions are of rheumatoid etiology. These conditions have additional shared characteristics, since they induce peripheral arthritis, clinically overlap and display familial aggregation. The primary representatives of this group are [1] [2]:

The aforementioned types of permanently seronegative arthritis are referred to also as spondyloarthropathies or spondarthritides, due to the fact that ankylosing spondylitis is a frequent comorbidity diagnosed in patients suffering from them.

Patient Information

Seronegative rheumatoid arthritis is a type of rheumatoid arthritis. Typically, when a person is diagnosed with rheumatoid arthritis, they are expected to test positive for the rheumatoid factor, an antibody that strongly confirms the presence of a rheumatic disease. Seronegative rheumatoid arthritis refers to any type of rheumatoid arthritis that does not involve the presence of the rheumatoid factor in the laboratory tests, but it still affects an individual.

Rheumatoid arthritis in general is an autoimmune type of arthritis. This means that it falls into the category of conditions for which the medical community has not yet pinpointed any definite causes and the organism is attacking itself. Various hypotheses and suggestions have been made over the years regarding the cause of these autoimmune diseases, but have all failed to be definitively confirmed.

Seronegative rheumatoid arthritis is not a single disease; on the contrary it is a general term applied to any type of rheumatoid arthritis without a positive rheumatoid factor, as mentioned before. The most common representatives of this disease group are ankylosing spondylitis and reactive arthritis.

There are generally various subtypes of seronegative rheumatoid arthritis, as these conditions can involve inflammation or no inflammation, they can affect a single joint or multiple joints and they can cause arthritic symptoms in various sites. The hips are the regions mostly affected, followed by the knees, back, wrists or fingers, depending on the condition. Also depending on the type of arthritis, an individual may feel the affected regions stiff and painful when they wake up, or late at night, due to the strain everyday movements exert on the body. Arthritis can be accompanied by symptoms from the eyes, lungs, heart or the genital tract.

References

Article

  1. Lambert JR, Wright V, Rajah SM, Moll JM. Histocompatibility antigens in psoriatic arthritis. Ann Rheum Dis. 1976 Dec;35(6):526-30. 
  2. Leonard DG, O'Duffy JD, Rogers RS. Prospective analysis of psoriatic arthritis in patients hospitalized for psoriasis. Mayo Clin Proc. 1978 Aug;53(8):511-8.
  3. Khan MA. Update on spondyloarthropathies. Ann Intern Med. 2002 Jun 18. 136(12):896-907. 
  4. Sahlberg AS, Granfors K, Penttinen MA. HLA-B27 and host-pathogen interaction. Adv Exp Med Biol. 2009. 649:235-44.
  5. Savolainen E, Kettunen A, Närvänen A, et al. Prevalence of antibodies against Chlamydia trachomatis and incidence of C. trachomatis-induced reactive arthritis in an early arthritis series in Finland in 2000. Scand J Rheumatol. 2009. 38(5):353-6.
  6. Zochling J, Smith EU. Seronegative spondyloarthritis. Best Pract Res Clin Rheumatol. 2010 Dec;24(6):747-56.
  7. McGonagle D, Emery P. Enthesitis, osteitis, microbes, biomechanics, and immune reactivity in ankylosing spondylitis. J Rheumatol. 2000 Oct. 27(10):2302-4. 
  8. Kaarela K, Jäntti JK, Kotaniemi KM. Similarity between chronic reactive arthritis and ankylosing spondylitis.A 32-35-year follow-up study. Clin Exp Rheumatol. 2009 Mar-Apr. 27(2):325-8.
  9. Lee DA, Barker SM, Su WP, Allen GL, Liesegang TJ, Ilstrup DM. (1986). The clinical diagnosis of Reiter’s syndrome. Ophthalmology. 1986 Mar;93(3):350-6.
  10. Ostler HB, Dawson CR, Schachter J, Engleman EP. Reiter’s syndrome. Am J Ophthalmol. 1971 May;71(5):986-91.
  11. Barth WF, Segal K. “Reactive arthritis (Reiter’s syndrome).” Am Fam Physician. 1999 Aug;60(2):499-503, 507.
  12. Petersel DL, Sigal LH. Reative arthritis. Infect Dis Clin North Am. 2005 Dec;19(4):863-83.

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Last updated: 2018-06-22 01:07