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Arthritis

Contents


Types of Arthritis

Arthropathy (joint disease), including Arthritis and Arthralgias are the most common Extraintestinal Manifestation (EIM) seen in Inflammatory Bowel Disease (IBD), and is more common in patients with disease in the Large Intestine / Colon than those with disease restricted to the Small Bowel. With patient disease rates up to 53%.[56][57], Arthropathy can range in severity between Asymptomatic to severe Pain and Joint Destruction. Certain types of Arthropathy are more common in patients with Crohn's Disease, Lymphocytic Colitis, Mastocytic Enterocolitis, and/or Ulcerative Colitis than others and may or may not include Enthesitis.
It is important to be aware of the symptoms in order to obtain an early diagnosis and appropriate treatment. There are many different types, causes, and treatments for Arthropathy. This list should not be considered exhaustive.

Ankylosing Spondylitis (AS)

Ankylosing Spondylitis (AS) is a Chronic type of Arthritis affecting the Spine and Sacroiliac joints. It primarily affects males in their mid 20s, although females can also be affected by the disease. [40] Pain is typically worse during periods of immobility (such as at night or in the morning). Risk factors include: Family History of AS, Genetics, and frequent Gastrointestinal (GI) or Urinary Tract Infections. [32] Many people with AS also have Crohn's Disease or Ulcerative Colitis.

Common Symptoms:
Anemia (mild to moderate)[32]
Fatigue [32]
Lower Back / Buttocks Pain and Stiffness [32]
Pain in Joints may spread up the Spine, Neck and Peripheral Joints[32]
Uveitis

Joints Affected:
Rarely, patients with AS have pain in small joints or joints of the arm. Typically joints affected by AS include:
Hip[32]
Knee[32]
Neck[32]
Ribs[32]
Sacroiliac Joint (Typical Presenting Joint) [32]
Shoulder[32]
Spine[32]

Laboratory and Diagnostic Tests:
- Anemia (Mild)
- ESR (Erythrocyte Sedimentation Rate) - shows presence of Inflammation but is not specific for AS nor is it elevated in all AS patients[32]
- MRI (or X-Ray) showing damage to the Sacroiliac Joint (may not be seen in early disease) [32]
- RF (Rheumatoid Factor) - Negative[32]
- ANA (Anti Nuclear Antibody) - Negative[32]

Treatment:
Acupuncture[32]
Biologics (Anti - Tumor Necrosis Factor (TNF) Agents) [40] [32]
Diet[32]
DMARDs[32]
Exercise[32]
Massage[32]
NSAIDs **To be used with caution in patients with GI Disease[32]
Surgery[32]
Transcutaneous Electrical Nerve Stimulation (TENS)[32]
Yoga[32]

Fibromyalgia (FMS)

Fibromyalgia is a disease that causes Fatigue and Pain, along with disturbances in normal Sleep. It is not yet understood what causes the disease, but it appears to be the result of many factors, including: the Immune Response, Nervous and Vascular Systems, Genes and Hormones. It affects approximately 3.4% of Women and 0.5% of Men. Fibromyalgia is often difficult to diagnose because Laboratory Tests are typically normal and symptoms are vague. Joint pain and Stiffness are often Chronic and Diffuse. Fibromyalgia is exacerbated by Stress which can disrupt normal sleep patterns. Stress and Sleep disruption cause a vicious cycle in Fibromyalgia, and can disrupt normal levels of hormones, neurotransmitters, and growth factors feeding into pathology of the disease. It is often found in patients with other diseases, especially those that are Autoimmune.[58]

Reduced blood flow has been shown in certain areas of the brain in Fibromyalgia patients. Treatment with Amitriptyline can help normalize blood flow in these areas.[58]

Bacterial and Viral infections appear to trigger Fibromyalgia symptoms, and may be related to the Immune Response to Infection and/or the infecting organism itself. Other triggers include: Chemical Exposures, Injury, and Vaccination. However, in most patients there is no known trigger.[58]

Symptoms:
Anxiety
Depression - also causes worsening of Fibromyalgia symptoms (relates to low Serotonin levels)
Diabetes - in some patients
Fatigue
Insomnia
Inflammatory Bowel Disease (IBD) - in some patients
Irritable Bowel Syndrome (IBS) - in some patients
Joint Pain
Joint Stiffness
Mood / Psychiatric / Temperment disorders - in some patients
Raynaud's Disease - in some patients
Temperature Intolerance (Heat or Cold Intolerance) - in some patients
"Tender Points"

Joints Affected:
Fibromyalgia pain affects the muscles and skeleton and is typically described as diffuse, deep, and burning. It can come and go and can move to different areas of the body. Certain areas of the body, called "Tender Points" are considered painful when pressure is applied. Diagnosis requires widespread, diffuse pain to be present for a minimum of three months and 11 of the 18 "Tender Points" to be considered painful with pressure (see Figure 1 based on data from [58])
Figure 1: "Tender Points" in Fibromyalgia (Based on data from [58])


Laboratory Tests:
Laboratory tests are often normal in Fibromyalgia patients and there are no specific Laboratory tests that are diagnostic for the disease. Typical tests that may be ordered include:
C Reactive Protein (CRP) - typically ordered, but positive result is not diagnostic for Fibromyalgia
Erythrocyte Sedimentation Rate (ESR) - typically ordered, but not diagnostic for Fibromyalgia
Serotonin - Low levels may be found, and contributes to pathology, but is not diagnostic
Thyroid Hormone - Hypothyroidism can mimic Fibromyalgia symptoms

Treatment:
Acupuncture
Amitriptyline - increases blood flow in certain areas of the brain (reduced blood flow has been shown in these brain areas in Fibromyalgia patients).
Anti-Depressants (low dosage for pain)
Anti-Epileptics
Anti-Inflammatory medications
Balneotherapy
Duloxetine
Exercise (low impact, aerobic)
Gabapentin (for pain)[44]
Milnacipran
NSAIDs offer limited benefits and are not often used
Opiates are typically ineffective in Fibromyalgia patients
Pregabalin (for pain)[44]
Sleep Restoration
SSRIs
Stress Reduction (stress exacerbates symptoms)
Tramadol

Infectious Causes of Arthritis

Arthritis can be caused by multiple different Infectious agents, including:
Bacteria
Rheumatic Fever
Salmonella
Staphylococcus
Streptococcus

Fungi
Blastomycosis
Candida albicans
Coccidiomycosis
Cryptococcosis
Histoplasmosis
Sporotrichosis

Mycobacteria
Joint tuberculosis

Virus
Hepatitis B
Influenza virus
Rubella

Juvenile Ideopathic Arthritis

Juvenile Ideopathic Arthritis (JIA) is Arthritis which occurs for 6 or more weeks in children under the age of 16. May be progressive resulting in disability from joint damage.[16]

Common Symptoms:
Fever (possible) [40]
Joint Pain[40]
Joint Stiffness[40]
Joint Swelling[40]
Rash (possible) [40]
Uveitis [40]

Joints Affected:
Three Subtypes of Juvenile Ideopathic Arthritis exist:[40]
- Pauciarticular (Oligoarthritis) - Less than five joints
- Polyarticular - Five or more joints
- Systemic - Arthritis with Fever and Rash

Laboratory and DiagnosticTests:
There is no one blood test that will diagnose JIA, however certain blood tests can help differentiate between different forms of the disease. These include:
ANA (Anti Nuclear Antibody) - May help predict eye disease[45]
CCP - Can help predict development of RA later[45]
ESR (Erythrocyte Sedimentation Rate) - Shows Inflammation is present[45]
RF (Rheumatoid Factor) - Rarely found in patients with JIA[45]
Later in the course of the disease, X - Rays can indicate the level of damage to the joints.[45]

Treatment:
Biologics [40]
DMARDs [40]
Methotrexate [40]
NSAIDs [40] **Used with caution in patients with GI disease[44]
Steroid Injections (systemic therapy usually avoided)[40]

Lupus, or Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus (SLE) is an Autoimmune disease which causes symptoms in many organs of the body. Certain parts of the Immune System see body tissues as pathogens and can cause destructive effects. The pathology of SLE is not completely understood but the dysregulation of certain Cytokines, such as: Interleukin 6 (IL6), Interleukin 10 (IL10), and Tumor Necrosis Factor (TNF) appear to be contributing factors. Symptoms can occur within or around the joints and cause Arthralgia or Arthritis. Lupus symptoms typically begin in the 20s - 30s, although it can occur at any age. Ten times more women are affected by the disease than men. Estrogens, estrogen metabolites, and certain defects in the Estrogen metabolic pathways appear to exacerbate the disease.[54] Although Arthritis and Joint pain occurs in about 90% of patients with Lupus, joint pain can result from Myalgia and/or Tendonitis. In some patients, joint pain can be caused by Bone Fracture from Osteoperosis, Septic Arthritis, or Osteonecrosis, especially if this pain is severe.[51] Fibromyalgia, may co-exist with Lupus, and can add to painful symptoms.[51]

Symptoms:
- Abdominal Pain[53]
- Arthritis (in two or more joints)
- Blood Disorder Hemolytic Anemia, Low Platelet Count, or Low White Blood Cell (WBC) Count]
- Discoid Rash - Rash with raised red patches, scaling, and plugged hair follicles[53]
- Fatigue
- Fever (low grade)
- Hair Loss
- Heart Pericardium Inflammation
- Joints Swollen, Stiff and/or Painful
- Kidney Dysfunction[53]
- Lung Inflammation
- Malar Rash - "Butterfly" rash on cheeks and nose[53](see Malar Rash ("Butterfly Rash") Picture Below
- Mouth or Nose Sores (usually painless)[53]
- Protein in Urine
- Photosensitivity Rash - Rash due to Sun Exposure[53]
- Serositis - Inflammation of tissue covering internal organs[53]
- Siezures or Psychosis[53]
- Swollen Ankles
Malar Rash ("Butterfly Rash")
A Malar Rash or "Butterfly Rash" is depicted below:



Joints Affected:
Lupus typically affects joints in a symmetrical fashion, particularly in the hands and wrists. Joint pain can move between different joints and usually lasts a few days. Joint damage in Lupus is typically less severe than RA, and does not usually cause bone erosion as RA can. Although joints may swell only slightly (or not at all), the pain is more severe than one would expect. About 5-10% of patients have misalignment of the fingers, called Jaccoud's Arthropathy.[51] Jaccoud's Arthropathy is not specific to Lupus and can be seen in Rheumatic Fever, Psoriatic Arthritis, Inflammatory Bowel Disease, Pyrophosphate Arthropathy, etc.[52] This can be correctable as it is often due to "loose" tendons or ligaments and not damage to the bone.[51]

Laboratory Tests:[30]
- Antinuclear Antibodies (ANA) - Positive (ANA is not specific to Lupus)
- Cardiolipin Antibodies (Antibody to cell membranes) - positive in 33% of Lupus patients (not specific to Lupus)
- Complete Blood Count (CBC) - Low Platelets, Low RBC, Low WBC
- Creatinine
- C Reactive Protein (CRP) - Inflammation marker (not specific for Lupus)
- dsDNA Antibodies - Positive
- Electrolytes
- Smith (Sm) Antibodies - Positive
- Urinalysis - Blood or Protein can be present in patients with Lupus (not specific for Lupus)[53]

Treatment:[50]
Avoid Estrogen and Estrogen - containing medications
Avoid Sun Exposure as it can trigger a Lupus Flare
Benlysta (belimumab)
CellCept (Mycophenolate)
Cyclosporine
Cytoxan (Cyclophosphamide)
Deltasone
DMARDs[51]
Exercise
Imuran (Azathioprine)
NSAIDs
Orencia
Plaquenil (Hydroxychloroquine)
Prednisone
Rituxan

Osteoarthritis

Osteoarthritis (OA) is the most common form of arthritis.[49] OA is a degenerative disease which occurs following wear or injury to joint cartilage which is not effectively repaired. Loss of cartilage causes bone - on - bone contact, leading to further damage and pain. OA can also cause bone overgrowth or bone spurs. OA most often affects women and people of advancing age (usually after 40), or who are obese. Joint injury and repeated motion will also increase OA risk. Persons who do not get enough exercise are at higher risk for developing OA.[46][47] Certain defects in the Innate Immune Response are correlated with OA. Pathogen - Associated Molecular Patterns (PAMPs), from Microbes, and Danger - Associated Molecular Patterns (DAMPs), from stressed, dead or dying cells, stimulate and exacerbate the Inflammatory Response, including activation of Interleukin - 1 beta (IL1B) and NFkB, also seen at increased levels in many patients with Crohn's Disease.[48]

Common Symptoms:
Flexibility Loss [47]
Grating Sound in Joint[47]
Pain in the joint during or after movement or during pressure to the joint. [47]
Pain can be affected by weather (especially if cold and/or damp)[49]
Stiffness (especially after prolonged inactivity, such as in the morning) [47]

Joints Affected:
Hands
Hips
Knees
Lower Back
Neck

Laboratory Tests:
- C Reactive Protein (CRP) - Increased CRP levels are correlated with Inflammation and disease activity but is not a diagnostic test for OA
- Computed Tomography (CT)
- ESR - not increased in OA[49]
- MRI
- X-Ray

Treatment:
- Acupuncture
- Exercise (low or non-impact)
- Glucosamine and Chondroitin
- Hyalgan[TM]
- Joint Replacement
- NSAIDs
- Narcotics for Pain
- Occupational Therapy
- Physical Therapy
- Radionuclide Nuclear Medicine Bone Scan
- Steroid Injections
- Synovial Fluid Test - Synovial fluid is the liquid present in the joint. In OA patients, the numbers of White Blood Cells (WBC) are usually low, and fluid is clear (high WBC counts and cloudy fluid may suggest an infection rather than OA)
- Synvisc[TM]
- Temperature (heat or cold applied to joint)
- Topical cream or gel
- Ultrasound
- Weight Loss (if overweight)

Rheumatoid Arthritis (RA)

Rheumatoid Arthritis affects approximately 1% of the population. Although RA can affect any person of any age, it most often affects women between 40 - 60 years old. RA is a progressive disease characterized by Inflammation of the Synovial tissues and bone/joint damage.

Common Symptoms:
- Anemia (mild)[61]
- Arthritis in 3 or more Joints [60]
- Arthritis of the hands / wrists[60]
- Dry Eye (- 50% of patients)[61]
- Exercise (range of motion, mobility)
- Fatigue
- Fever (low grade)
- Joint Pain
- Joint Stiffness (especially in Morning lasting > 1 hour)[60]
- Joint Swelling
- Non-joint related disease is also common

Joints Affected:
- Hands and Feet on both sides of the body (Symmetrical Arthritis) are usually affected first and primarily include the small joints.[60]
- Rheumatoid Nodules

Laboratory Tests:
- C - Reactive Protein (CRP) [40][61]
- Cyclic Citrullinated Peptide (CCP aka ACPA) Antibody may diagnose RA earlier than RF Test
- ESR[61]
- Mutated Citrullinated Vimentin (MCV) Autoantibodies [5]
- Radiology shows Erosion or Periarticular Osteopenia[60][61]
- Rheumatoid Factor (RF) elevated in blood test in - 80% (but may be negative early in disease)[60]

Treatment:
Treatment is often a lifelong process and varies by disease severity, duration and treatment response. Often, medications include:
- Antioxidants[61]
- Biologics (with or without MTX) [6]
- DMARDs (with or without MTX) [6]
- Methotrexate (MTX) [6]
- Neuromodulators (as added therapy for pain management)[44]
- NSAIDs ** To be used with caution in patients with GI Comorbidities[44]
- Omega 3 Fatty Acids [61]
- Opioids (weak) for short term treatment of pain[44]
- Paracetamol [44]
- Steroids / Glucocorticoids (as an Anti-Inflammatory, not recommended for pain management)[44]
- Tricyclic Antidepressants (TCAs) as added therapy for pain management[44]

Sjögren’s Syndrome (SS)

Sjogren's Syndrome (SS), also known as Sicca Syndrome, is a Chronic autoimmune disease affecting many organs of the body (including, lung, kidney, thyroid, joints, etc). SS primarily affects women (approximately 90%) over the age of 40. An important aspect of SS is that glands making Saliva (Salivary Glands) and Tears (Lacrimal Glands) to not function properly, causing dry Mouth and Eyes. Some patients may also have Raynaud’s phenomenon, Vasculitis, or a particular type of cancer, called Lymphoma.[28][21] Sjogren's Syndrome may go undiagnosed for years. It is important to obtain an early diagnosis and treatment to minimize Sjogren's-related damage.

Common Symptoms:
- Candidiasis
- Dry Eyes, Mouth, Skin, Vagina
- Fatigue
- Joint Pain/Inflammation
- Myalgia (Muscle Pain)
- Numb or "Pins and Needles" feeling in Hands or Feet
- Swollen Salivary Glands

Joints Affected:

Laboratory Tests:
- Antinuclear Antibodies (ANA)
- Anti SSA
- Anti SSB
- Biopsy of Salivary Glands (showing Inflammation and Immune Cells)
- Rheumatoid Factor (RF)
- Schirmer Test - Measures Tear Production

Treatment:
Antifungal Medications
Artificial Tears / Ointments / Lubricants
Cevimeline.
Cyclophosphamide
Hydroxychloroquine
Methotrexate
NSAIDs ** To be used with caution in patients with GI Comorbidities
Pilocarpine
Sealing of Tear Ducts
Steroids

Spondyloarthropathy (SpA)

Spondyloarthropathies (SpA) refer to a group of different types of arthritis, including: Ankylosing Spondylitis (AS), Undifferentiated Spondyloarthritis, Reactive Arthritis (Reiter's Syndrome), Psoriatic Arthritis, IBD-Associated Spondyloarthritis and Juvenile Onset Spondyloarthritis. Although it may be Asymptomatic, up to 2/3 of patients with SpA may also have Gastrointestinal Tract Inflammation.

Common Symptoms / CoMorbidities:
Back Pain due to Inflammation (before the age of 40)
Buttock Pain
Cervix Inflammation / Infection (within month preceding Arthritis Symptoms)
Diarrhea (within month preceding Arthritis Symptoms)
Family History
Inflammatory Bowel Disease (IBD)
Psoriasis
Sacroiliitis Diagnosis
Urethra Inflammation / Infection (within month preceding Arthritis Symptoms)

Joints Affected:
Axial Joints
Enthesitis
Inflammation of Multiple Joints - Asymmetric Distribution, Mainly Lower Limbs
Sacroiliac Joint

Armor Criteria for Spondyloarthropathy[59]
CriteriaScore "Yes" ResponseEnter Your Score
Lower Back Pain (Nighttime) OR Lower Back Stiffness (Morning)1____
Pain in Multiple Joints (Asymmetric Joints)2____
Buttocks Pain (or Alternating Buttocks Pain)1 (or 2)____
Finger or Toe resembling "Sausage"2____
Painful Heel (or Heels)2____
Iritis (Eye Inflammation)2____
Inflammation or Urethra or Cervix in previous Month1____
Diarrhea in previous Month (or Current)1____
History (or Current) Psoriasis or IBD2____
X - Ray showing Sacroiliitis (Bilateral Grade > 2 or if Unilateral Grade>3)3____
HLA-B27 or Family History of AS, IBD, Psoriasis, Reactive Arthritis or Uveitis2____
Improvement of Joint Symptoms within 48 hours of NSAID Therapy2____
Total Score (if 6 or more may indicate Spondyloarthropathy)____

Exposures and Comorbidities

Arthritis is commonly seen along with other diseases, conditions, chemical exposures, or even IBD treatment, including:
* Alcoholism
* Asbestos Exposure[31]
* Bacteremia
* Behcet's Disease
* Celiac Disease
* Chondrocalcinosis
* Crohn's Disease (CD)
* Depression
* Fatigue
* Fistulas may cause bacterial infection of the joints (esp. sacroiliac joints)
* Infection (including Bacterial, Fungal, Parasitic, Viral)
* Inflammation
* Inflammatory Bowel Disease (IBD)
* NOD2 / CARD15 Gene Mutation - Patients with Sacroiliitis were more likely to have the NOD2 / CARD15 Gene Mutation than persons that did not have Sacroiliitis.
* Pain
* Prednisone can cause Osteonecrosis of the bone (Avascular Bone Necrosis)
* Pseudomembranous Colitis
* Silicon Exposure [31]
* Synovitis
* Whipple's Disease

Arthritis Treatments

Analgesics
Capsaicin (Topical) - Has been shown to reduce pain due to Osteoarthritis and Rheumatoid Arthritis. However, skin irritation can develop if used for long periods of time (over 2 weeks).[8]
Nefopam[44]
Anticonvulsants
Carbamazepine
Gabapentin[44]
Lamotrigine
Levetiracetam
Oxcarbazepine
Phenytoin
Pregabalin[44]
Sodium Valproate
Tiagabine
Topiramate
Antidepressants
B Cells
- Rituxan (Rituximab) Mouse/Human Antibody IV Infusion every 4-6 Months (after loading dose)
Cannabis
COX-2 Inhibitors
CTLA-4
- Orencia (Abatacept) IV Infusion Monthly or Injections Weekly (after loading dose)
Disease Modifying AntiRheumatic Drugs - DMARD
- Antibiotics - Minocycline
- Antimalarials -- (Chloroquine phosphate, Chloroquine sulphate, Hydroxychloroquine)
- Arava (leflunomide) Arava
- Auranofin
- Azathioprine
- Cyclophosphamide
- Cyclosporine
- Methotrexate
- Myocrisin
- Sulphasalazine
Hyaluronate
Euflexxa (Sodium Hyaluronate)
Hyalgan (Sodium Hyaluronate)
Orthovisc (Hyaluronan)
Supartz (Sodium Hyaluronate)
Synvisc (Hylan G-F 20)
Synvisc ONE (Hylan G-F 20)
Integrin (alpha 4 Integrin Subunit)
Tysabri (Natalizumab) IV Infusion Monthly *Limited Availability due to Progressive Multifocal Leukoencephalopathy (PML) Risk*[40][42]
Integrin (alpha L), ITGAL
Raptiva (Efalizumab) Injection Weekly *No longer available due to PML risk* [40][43]
Interleukin - 1 Receptor biologics
- Kineret (Anakinra) Injection Daily [17]
Interleukin - 6 Receptor
- Actemra (Tocalizumab) Human Antibody IV Infusion Every 2-4 Weeks [Actemra]
Interleukin - 12; Interleukin - 23
Stelara (Ustekinumab) Human Antibody Injection Every 3 Months (after loading dose)
Janus Kinase 3 (JAK3)
Xeljanz (Tofacitinib) [24]
NSAIDs
Celebrex
Mobic (meloxicam)
Voltaren (Diclofenac)
Salicylates
Aspirin55
Steroids
- Cortisone Injection
- Prednisone / Prednisolone
T Cells
Amevive (Alefacept) Injection Weekly [Amevive]
TNF Biologics
- Cimzia (Certolizumab pegol) Human Fab Fragment Injection Biweekly or Monthly
- Enbrel (Etanercept) TNFa receptor-Human IgG1 Fc Fragment Injection 1x or 2x Weekly
- Humira (Adalimumab) Human Injection Weekly or Biweekly (after loading dose)
- Remicade (Infliximab) Mouse/Human IV Infusion every 6 or 8 Weeks (after loading dose)
- Simponi (Golimumab) Human Injection Monthly
Vitamins and Supplements
Curcumin (Turmeric)
Glucosamine [10]
Omega 3 Fatty Acids / Fish Oil

Clinical Trials for Arthritis

Clinical TrialTrial IdentifierLink
25-hydroxyvitamin D and Fatigue: The VITALITY StudyNCT01718925Link
Analysis of Birth Outcomes of Swedish and Danish Women Exposed to Remicade With IBD, RA, Psoriatic Arthritis, AS, and PsoriasisNCT00658827Link
Certolizumab Pegol for the Treatment of Patients With Active Rheumatoid Arthritis (RA)NCT01577264Link
Long Term Safety Study of Infliximab (Remicade)NCT00261976Link
Cannabis for Inflammatory Bowel DiseaseNCT01040910Link
OTIS Autoimmune Diseases in Pregnancy ProjectNCT01086059Link
Sirolimus for Autoimmune Disease of Blood CellsNCT00392951Link

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