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.

• Pain

  Secondary end points were pain and functional status at 6-12 months, three month rheumatologist assessed joint count, pain, and arthritis activity, and treatment efficacy in those with previous exposure to chlamydia. [ncbi.nlm.nih.gov]

  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 [symptoma.com]

  […] to endure the pain. [interhomeopathy.org]

  It is a disabling and painful condition which can lead to substantial loss of mobility due to pain and joint destruction. [dailystrength.org]

• Inflammation

  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. [symptoma.com]

  These indicate that the patient is seropositive and that they possess the antibodies that cause an attack on joints and lead to inflammation. [rheumatoidarthritis.org]

  Doctors often prescribe steroids as well to get the inflammation under control. DMARDs restrict the immune system and help to preserve joints by blocking the inflammation that can slowly destroy the joint tissue in people with RA. [medicalnewstoday.com]

  The use of proteolytic enzymes such as pHi-Zymes to reduce inflammation systemically and reduce the incidence of cirulating immune compelxes. Supplementation with Omega-3 fatty acids can also help with inflammation. [jonbarron.org]

• Fatigue

  I was stiff most of the day and the fatigue was worsening. The fatigue is the hardest part for people to understand. I describe it like having the flu. I was prescribed prednisone steroids to check the inflammation. [livingwithra.wordpress.com]

  In the absence of any constitutional symptoms (fatigue, malaise, loss of appetite, night-sweats or low grade fever, etc.), it would appear that the condition is non-inflammatory and likely to be mechanical. [doctor.ndtv.com]

  Common signs and symptoms of rheumatoid arthritis, states the Arthritis Foundation, include warmth, swelling, pain and inflammation in your affected joints, fatigue, mild fever and reduced appetite. [livestrong.com]

  Fatigue, fever, and joint pain frequently occur. [arthritis-health.com]

• Asymptomatic

  Asymptomatic urethritis is not uncommon. Conjunctivitis most commonly accompanies reactive arthritis following salmonellosis or shigellosis. [symptoma.com]

  The initial infection can often be asymptomatic. Relationship between psoriatic skin disease and arthritis The activity of the two is unrelated and one may flare without the other. Enteropathic arthropathy is more closely related. [brainscape.com]

  Other Extra- articular Manifestations • Apical pulmonary fibrosis, mostly asymptomatic and typically observed in patients with substantial disease duration, has been noted in a small percentage of AS patients 40. [slideshare.net]

  […] affecting DIPJs particularly Chronic poly arthritis may develop with relapsing and remitting caurse eventually ® subchondral collapse and permanent disability Myopathy CNS & PNS involvement Skin granulomas (erythema nodosum) Respiratory Cough and dyspnoea Asymptomatic [flinders.edu.au]

• Constitutional Symptom

  In the absence of any constitutional symptoms (fatigue, malaise, loss of appetite, night-sweats or low grade fever, etc.), it would appear that the condition is non-inflammatory and likely to be mechanical. [doctor.ndtv.com]

  symptoms AV block Characteristics of AS back pain Insidious onset before 40yrs for longer than 3months Associated with early morning stiffness and improves with exercise May have nocturnal pain Degenerative versus ankylosing spinal changes Degenerative [brainscape.com]

  Prosthetic fungal arthritis tends to have an indolent course with symptoms, such as pain, swelling and limited range of motion of the affected joint, occurring as late as five years after surgery. Fever and constitutional symptoms are rare. [hopkinsarthritis.org]

  Constitutional symptoms such as weight loss, night sweats, fever, and fatigue are also more common with systemic illnesses. Patient history, including social history, can provide further insight into the patient's physiologic state. [aafp.org]

• Nausea

  After three weeks on that drug, my body clearly told me it didn’t like it…constant nausea, headache, feeing like a truck ran over me, etc. So, off to the doctor I went again. [livingwithra.wordpress.com]

  The most common gastrointestinal side effects of opioid medicines like MS Contin are constipation, nausea, vomiting, and dry mouth. Stomach cramps — perhaps this is what you mean by gas pains — are less common but can be very bothersome. [everydayhealth.com]

• Vomiting

  The most common gastrointestinal side effects of opioid medicines like MS Contin are constipation, nausea, vomiting, and dry mouth. Stomach cramps — perhaps this is what you mean by gas pains — are less common but can be very bothersome. [everydayhealth.com]

• Visual Impairment

  (in contrast to JRA it is self limiting and rarely leads to visual impairment.) - Enthesopathy: - pain at ligament and tendon insertions; - seen frequently, may occur before back symptoms. - occurs in: metatarsal heads, plantar fascia, achilles tendon [wheelessonline.com]

• Arthritis

  Seronegative rheumatoid arthritis is a type of rheumatoid arthritis. [symptoma.com]

  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]

  Entry H01507 Disease Name Seronegative arthritis Subgroup Ankylosing spondylosis Undifferentiated spondylarthritis Reactive arthritis Psoriatic arthritis Enteropathic arthritis Description Seronegative spondyloarthropathies (SpA) represent a group of [genome.jp]

• Morning Stiffness

  Doctors Rely on Symptoms to Diagnose Seronegative RA, Not Just the Results From Blood Tests Since blood work doesn’t tell the whole story, your doctor will want to find out if you’re experiencing these key symptoms : Morning stiffness for more than an [everydayhealth.com]

  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. [symptoma.com]

  Morning stiffness in seronegative form of the disease is less frequent and is less acute. [yourhealthyjoints.com]

  stiffness, Fatigue (lack of sleep due to pain at night) Ankylosis --> Increasing stiffness and reduced ROM and increasingly abnormal posture How to quantify spinal involvement in AS Measure the occiput to wall distance (increases as posture changes) [brainscape.com]

• Oligoarthritis

  Other forms of seronegative arthritis predominantly involve oligoarthritis. Investigations. There are no specific laboratory tests. Acute-phase reactants like the ESR and C-reactive protein may be elevated. Rheumatoid factor is usually negative. [medicine.jrank.org]

  A 27-year-old female lowland gorilla developed an asymmetric oligoarthritis 3 months post-partum. There was no evidence of an antecedent gastrointestinal or genitourinary infection. Serum was negative for rheumatoid factor and antinuclear antibody. [ncbi.nlm.nih.gov]

  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). [symptoma.com]

  Common characteristics [ edit ] These diseases have the following conditions in common: Seronegative (i.e. rheumatoid factor is not present) [5] They are in relation to HLA-B27 [8] Inflammatory axial arthritis, generally sacroiliitis and spondylitis [5] Oligoarthritis [en.wikipedia.org]

• 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]

  Arthritis causes inflammation (swelling, redness and pain) in your body’s joints. It’s common in people as they get older. [webmd.com]

• Knee Effusion

  Musculoskeletal exam reveals moderate size left knee effusion that is warm and limited range of motion. [rheumatology.org]

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.

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.

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.

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].

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%.

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.

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.

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]:

• Psoriatic arthritis
• Reactive arthritis (Reiter's syndrome)
• Uncomplicated ankylosing spondylitis
• Arthropathies linked to gastrointestinal autoimmune diseases (ulcerative colitis or Crohn disease)

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.

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.

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