Lecture 169 Spondyloarthropathies: Ankylosing Spondylitis, Psoriatic Arthritis, Reactive/Enteropathic Arthritis and HLA-B27......and Adult Still's Disease

•1. ***A diagnosis of exclusion!

How do you diagnose Adult Still's Disease?

*One of the most common ethnic groups with AS are those of Northern European descent with a *male:female ratio of 3:1......usually presenting with chronic back pain before the age of 40.

What ethnic group is most commonly impacted by Ankylosing Spondylitis?

1. *50-75% have elevated ESR/CRP 2. **Positive HLA-B27 in most cases 3. Elevated alkaline phosphatase (from bone) in 13% 4. Occasional normo/normo anemia of chronic disease B. Radiologic tests 1. Sacro-iliac joints with joint space narrowing, sclerosis or erosive change. 2. Spine- *squaring of vertebral bodies from bone erosion, *syndesmophytes and *ankylosis of facet joints.......eventual "bamboo spine".........up to 14% can get atlanto-axial subluxation C1-C2

How do you diagnose Ankylosing Spondylitis (AS)?

A. Small bowel biopsy B. Serology (Can be ordered as a "Celiac Panel", with many of the following tests, or they can be ordered separately too) 1. Anti-endomysial IgA antibody (sens 85-98% and spec 97-100%) 2. Anti-tissue transglutaminase IgA antibody (sens 90-98%, spec 97-100%) 3. Anti-deamidated gliadin peptide antibody a. IgA- sens 94%, spec 99% b. IgG- sens 92% and spec 100% 4. Anti-gliadin antibody IgA and IgG (sens 85%, spec 85%) ****path improves and antibodies resolve on a gluten-free diet.....in patients with IgA deficiency (3% with Celiac dis) more reliance should be placed on IgG tests.

How do you diagnose celiac disease?

Non-pharm- 1. Smoking cessation 2. PT 3. Depression screening/psychosocial support Pharm- 1. *NSAIDs 2. DMARDs- not helpful 3. *TNF-alpha inhibitors (see Rheumatologic Drugs PowerPoint) 4. IL-17 monoclonal antibodies 5. JAK inhibitors 6. Thalidamide Surgery- a big time procedure to go through with this disease

How do you treat Ankylosing Spondylitis?

A. NSAIDs (slow, less satisfactory than in ARF) B. Steroids C. Prophylaxis against recurrence with antibiotics for >/= 1 year (c/w ARF, given for >/= 10 years). ***monitor closely for 1 year, some may eventually develop cardiac issues (6% develop mitral valve disease) or other symptoms/signs to fit them into an ARF or other diagnosis (autoimmune, Lyme dis, etc).

How do you treat Post-Streptococcal Reactive Arthritis?

A group of arthritic, inflammatory diseases that attack the spine, sacro-iliac joints, peripheral joints, tendons and where the tendons/ligaments attach to the bone (entheses). These diseases may also affect almost any organ system in the body, especially the eyes, skin/mucous membranes/soft tissues, GI and GU tracts.

What are Spondyloarthritides?

*At 60% increased risk for cerebrovascular mortality and 50% increased risk for vascular mortality.

What are patients with Ankylosing Spondylitis at risk for?

A. **Chlamydia trachomatis- the most common associated disease B. *Salmonella of various servovars C. *Shigella flexneri > S. dysenteriae > S. sonnei D. *Campylobacter jejuni E. *Yersinia enterocolytica and Y. pseudotuberculosis F. *Clostridiodes (Clostridium) difficile G. Others, less commonly associated, Chlamydia pneumoniae, Ureaplasma urealyticum, Mycoplasma genitalium, E. coli, Bacillus Calmette-Guerin (BCG)

What are the infectious etiologies of Classic Reactive Arthritis?

1. **ESR/CRP- marked elevations 2. **Ferritin- marked elevations in 70% (hepatocytes reacting to inflammatory cytokines can increase ferritin synthesis), it is an acute phase reactant....*on Boards, if they present a febrile patient and give you a super high ferritin result, then think adult Still's disease! (ferritin not typically something checked unless Fe deficiency, iron overload or Still's disease is suspected) 3. *Usually leukocytosis, >/= 15k, *poly predominance......leukopenia with associated HLH 4. *Anemia with Hgb of </= 10 in most patients 5. *Increased LFTS and LDH in 75% 6. *Positive RF/ANA/CCP in < 10% 7. Inflammatory synovial fluid (mean WBC 13k) 8. X-rays show non-erosive narrowing (esp c-mc and intercarpal joints)

What are the lab findings in Adult Still's Disease?

1. *25-30% get acute anterior uveitis (inflammation of the pigmented layer of the eye that lies between the inner retina and the outer sclera/cornea....includes the iris, ciliary body and choroid).....presents with acute eye pain, photophobia and blurred vision, tends to be unilateral and recurrent....can lead to glaucoma and cataracts. 2. Inflammatory bowel disease- ileal and colonic mucosal inflammation, frequently asymptomatic, can be found histologically in 50%. 3. Psoriasis in 10%, and these patents tend to have concomitant peripheral arthritis issues too. 4. Cardiovascular disease- aortic root issues cause AI in 10% and increased conduction abnormalities, coronary artery disease plus venous thromboembolism.....see "E" in the intro section. 5. Pulmonary- Mechanical restrictive lung disease is common, and apical fibrosis is common to see radiographically. 6. Occasional IgA nephropathy and renal amyloidosis may develop. 7. Low-grade fevers may be present intermittently or chronically

What are the other clinical effects of ankylosing spondylitis?

Fatigue, anemia, diarrhea, abdominal pain/cramps, bloating (often confused initially with irritable bowel syndrome), weight loss......**dermatitis herpetiformis, neuropathy (from vitamin malabsorption) and growth failure can be seen.

What are the symptoms of celiac disease?

1. Peripheral arthritis- a. Type I arthropathy- *acute and *oligoarticular, nonerosive and often involves large joints such as the *knees.....self-limited, in 90% lasts under 6 months......*often associated with IBD flares....occurs in 5% of those with IBD. b. Type II arthropathy- *polyarticular and nonerosive with MCPs being the most commonly affected joints, but can involve almost any joint......half of episodes are migratory......can be recurrent on and off for years.....*not associated with IBD flares....occurs in 3-4% of those with IBD.

What are the types of peripheral arthritis in Enteropathic Reactive Arthritis?

An inflammatory disorder characterized by **daily fevers (a cause of FUOs), **arthritis/arthralgias and an **evanescent rash (each in 75-95% of cases).....originally described by George Still in 1896.....used to describe adults with features similar to JRA, but who do not fulfill criteria for classic RA.

What is Adult Still's Disease?

Also known as Marie-Strumpell disease, Bechterew's disease, seronegative spondylitis (meaning RF-negative, no specific autoantibodies for this disease have yet been identified), **bamboo spine and axial spondyloarthritis

What is Ankylosing spondylitis also known as?

A. Immune, reactive scenarios after Strep infections that can occur ***after Group A Streptococcus, and *occasionally after Group C and Group G Streptococcus, infections. Due to molecular mimicry or immune complex disease. These include: 1. **Acute Rheumatic Fever (ARF)- 10-28 days after pharyngitis, *see pre-reading primer on ARF......associated with migratory arthritis. 2. **Post-Streptococcal Arthritis- 1-10 days after pharyngitis, associated with non-migratory arthritis. 3. Post-Streptococcal Glomerulonephritis- 1-3 weeks after pharyngitis or 3-6 weeks after skin/soft tissue infection. 4. PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) 1-4 weeks after pharyngitis.

What is Post-Streptococcal Reactive Arthritis?

Inflammatory arthritis of the sacroiliac joints.

What is Sacroilitis?

Inflammatory arthritis of the spine.

What is Spondyloarthritis?

An arthritis which develops soon after, or during, an infection elsewhere in the body......but which the microorganisms cannot be recovered from the joint.

What is classic reactive arthritis?

A. **Fever- usually once daily fever spikes (quotidian), sometimes twice daily (double quotidian) B. **Rash- evanescent ***salmon-colored (Boards!) mac/mac-pap, nonpruritic.....tends to come on with fever and go away with defervescence. Usually on trunk/extremities....can involve palms/soles and face. May have a "Koebner phenomenon" where rash may come on in areas where skin is stroked or in areas of pressure from tight clothes (beltline, bra strap regions). C. **Arthralgia/arthritis- can evolve over months into a destructive polyarthritis...knees > wrists (may fuse) > ankles > elbows > PIPs > shoulders. D. Other manifestations: 1. Myalgias- without weakness, often worse during fevers 2. Pharyngitis- severe, nonsuppurative is common.....may be associated with cricothyroid perichondritis on MRI 3. Liver disease- common to see modest LFT elevations, +/- hepatomegaly 4. Card-pulmonary disease- pericarditis, pleural effusions, transient pulmonary infiltrates with symptoms of serositis 5. Lymphadenopathy- ½, mild, slightly tender, reactive hyperplasia on histopath 6. Splenomegaly- 1/3-1/2 7. Macrophage activation syndrome- can be seen in around 12%, also termed *hemophagocytic lymphohistiocytosis HLH/reactive hemophagocytic syndrome.....associated sometimes with disease flares.....may have pancytopenia and very high triglycerides (*on path of bone marrow or liver RBCs can be seen phagocytized by macrophages) 8. GI- abd pain in 50%....nausea, anorexia and weight loss can be seen

What is the clinical presentation of Adult Still's Disease?

A. Peripheral arthritis 1. Acute onset **asymmetric, oligoarthritis of lower > upper extremities (esp. knees) or **sacroiliitis/spondylitis. This usually resolves in 3-5 months, but occasionally lasts chronically (15%). B. GU- **urethritis/dysuria is typical. There may also be pelvic pain, cervicitis, salpingo-oophoritis, prostatitis or cystitis. C. Ocular- **conjunctivitis.....less frequently anterior uveitis, episcleritis and keratitis. D. Constitutional- fever, fatigue, malaise or weight loss. E. Skin and soft tissue- 1. **Keratoderma blennorrhagicum- hyperkeratotic red skin lesions, waxy nodules, on palms and soles resembling psoriasis. 2. **Circinate balanitis- painless erythematous, serpiginous lesions beginning as vesicles then forming small shallow ulcers on the glans penis. 3. Nail lesions similar to psoriasis 4. *Dactylitis- "sausage" fingers and toes.....up to 40% of cases 5. *Enthesitis- common, especially in the heel

What is the clinical presentation of Classic Reactive Arthritis?

A. **Non-migratory (*unlike migratory arthritis seen in ARF) acute reactive arthritis presenting 7-10 days after GAS pharyngitis.....asymmetric in 60-70%.....50% resolve in 6 weeks. B. Has no other Jones criteria for ARF. C. Often more severe than that seen in ARF......may have fever. D. *Can be either persistent or recurrent, can be additive over time, and can affect large, small or axial joints (ARF predominately large joints)......usually mono- or oligoarthritis......sacroiliitis in only 1-2%.....enthesitis/dactylitis in < 1%. E. *Bimodal age group spikes....8-14 yo and 21-37 yo (c/w 5-15 for ARF)........I have seen it in people up to their 80s! F. *Minimal response to NSAIDs (unlike ARF that has a good response). G. Associated erythema nodosum and erythema multiforme are common (30%).

What is the clinical presentation of Post-Streptococcal Reactive Arthritis?

A. Asymmetric, inflammatory oligoarthritis (1-5 joints) 1. Most common joints involved are commonly the *DIP > PIP and MCP joints...."peripheral arthritis"......but can involve more central joints too 2. Symmetric, deforming arthritis (arthritis mutans) similar to RA.........+/- flexor tenosynovitis 3. Morning stiffness in 50%, with fatigue B. *Dactylitis and enthesitis (esp. Achilles tendon) like AS.......+/- pitting edema C. Nail changes....see Intro section for details D. +/- Spondylitis or sacroiliitis E. Ocular- 1. Uveitis 2. Conjunctivitis F. Skin- 2% of the population has psoriasis (80% have just mild-mod disease......</= 5% body surface area). In 85% the rash starts many years before the arthritis appears. 1. Red patches/plaques of skin with silvery scales, with most common sites being elbows/knees, low back and back of neck, scalp/face, palms/soles a. *Plaque psoriasis- is the most common (85-90%). b. Guttate psoriasis- causes many small, oval patches first appearing on the chest. c. Inverse psoriasis- smooth, red patches in skin folds (inguinal, breasts, axillae) d. Pustular psoriasis- rarer, with small, fluid filled blisters/pustules e. Erythrodermic psoriasis- rare, severe, affecting most of the body.

What is the clinical presentation of psoriatic arthritis?

1. **Low back pain- typically has at least 4 of the following 6: • a. Onset < 40 yo • b. Insidious onset • c. **Improvement with exercise • d. No improvement with rest • e. Pain at night (with improvement upon rising) • f. Morning stiffness 2. Neck pain- more prominent with disease progression 3. Impaired spine mobility 4. **Impaired posture- with hyperkyphosis (hunchback), often even in the first 10 years.....atlanto-axial subluxation at C1-C2 can occur spontaneously too. 5. Buttock pain- can be bilateral, common to be alternating side to side, due to sacroiliitis. 6. Hip pain- felt most in inguinal regions, sometimes leading hip flexion deformities. 7. Peripheral arthritis- most common in ankles, knees, hips, shoulders, sternoclavicular and TMJs. 8. *Enthesitis- pain/inflammation at attachment of tendons/ligaments to bone, especially where the Achilles tendon attaches at the heel. 9. *Dactylitis- "sausage digits" with diffuse swelling of toes/fingers. 10. ***"Bamboo spine"- the classic finding, develops when the outer fibers of the intervertebral discs ossify, forming *marginal syndesmophytes between adjoining vertebrae. 11. Osteopenia with fragility fractures

What is the musculoskeletal clinical presentation of patients with Ankylosing Spondyltits?

Historically this syndrome referred to a triad (Reiter's syndrome, Reactive Arthritis Triad) of **post-infectious arthritis, **urethritis and **conjunctivitis. However, there are many other issues that can develop that will be discussed later.

What is the triad of classic reactive arthritis?

Thought *autoimmune (from autoantibodies) and *autoinflammatory (activated immune cells, due to dysregulated secretion of pro-inflammatory cytokines, leading to consequent damage of host tissues) in nature

What is thought to cause Ankylosing Spondylitis?

****>/= 90% are HLA-B27+

What percentage of Ankylosing Spondylitis patients are HLA-B27+?

**8% of Caucasians, 5% of Latinos, 25% of Alaskan/Canadian Inuits (50% of the Haida tribe in the Alaskan panhandle), 4% of North Africans, 2% of African-Americans, 24% of Northern Scandinavians, 2-9% of Chinese and 0.1-0.5% of Japanese persons possess the gene encoding HLA-B27.

What percentage of Caucasians, Latinos, Alaskan/Canadian Inuits, North Africans, African-Americans, North Scandinavians, Chinese, and Japanese persons possess the gene encoding HLA-B27?

**30-80% are HLA-B27 positive......and HLA-B27 tends to be associated with the more severe and chronic forms of reactive arthritis.

What percentage of patients with Classic Reactive Arthritis are HLA-B27 positive?

*2% of the population has psoriasis

What percentage of the population has Psoriasis?

20-40% of people with psoriasis will have PA (you would think it is much more prevalent based on all the adds for meds on TV and in magazines!).......the longer or more severe the psoriasis, the more likely PA will develop......**psoriasis tends to precede PA by 7-10 years......in 10-15% of PA the arthritis comes first, however......those with psoriasis also have 4-8x increased risk to get Crohn's disease.

What percentage of the population that has Psoriasis will have Psoriatic Arthritis (PA)?

•*80-90% of those with PA have psoriatic nail changes (**nail pitting, separation of nail from nail bed = *onycholysis, *horizontal/vertical ridging and cracking, red spots in the lunula = mottled lunula, nail plate crumbling, *nail thickening = hyperkeratosis, areas of whitish discoloration = leukonychia or even loss of nail)........*only 40% of those with psoriasis alone have nail changes......can look like onychomycosis.

What percentage of those with PA have psoriatic nail changes?