11. Rheumatology and Musculoskeletal System Disorders

The Army Within

Our immune system fights against bacteria, viruses, fungi, protozoa, and rogue cancer cells. When the “army-within” fails to recognize our own cells and starts attacking them, it results in autoimmunity. Medications needed to treat autoimmune diseases, sadly, also weaken our own “army,” increasing risk of infections and malignancies.

11.1 Autoimmune Conditions: General Points

Sometimes it is helpful to think of autoimmune conditions in two broad categories:

Primary mediator of autoimmunity	Humoral B-cell autoimmunity	T-cell-mediated autoimmunity
Gender	Female predominant	Male predominant
Conditions^a	Rheumatoid arthritis (RA) Scleroderma SLE (systemic lupus erythematosus) Primary biliary cirrhosis Autoimmune hepatitis Sjögren’s syndrome Myositis syndrome Autoimmune thyroiditis	Primary sclerosing cholangitis Psoriasis Ankylosing spondylitis Inflammatory bowel disease—ulcerative colitis Reiter’s syndrome or Reactive arthritis
Serological tests	Mostly seropositive, e.g., antinuclear antibody (ANA), rheumatoid factor (RF)^b antimitochondrial antibody, anti-SSA, anti-SSB	Mostly seronegative, but may be p-ANCA positive Associated with HLA-B27
Associated condition	Increased risk of non-Hodgkin lymphoma and Raynaud phenomenon
General treatment strategy strategy	Flare-ups usually can be treated with steroids. In moderate-severe persistent disease, use steroid-sparing agents, such as methotrexate, azathioprine, mycophenolate, etc. As it takes some time for these to work, steroids are used as a “bridging” treatment.
^aPatients with one condition have increased risk of other conditions in the same group. For example, patients with RA have increased risk of Sjogren: patients with psoriasis have increased risk of ankylosing spondylitis.
^bNote: ANA and RF are not only found in SLE and rheumatoid arthritis, but also in other autoimmune conditions and also in females and old patients with no connective tissue disease. Hence, presence of ANA and RF in serum is very nonspecific.
CCS		Dx
An old patient with positive RF and ANA, but no other features suggestive of inflammatory disorder		Normal
Positive ANA, RF, and symmetrical arthritis of hand-joints with deformity		RA

MRS

PAIR of B27

When asked about the most common cause (MCC) of death in a specific condition (e.g., what is the MCC of death in SLE, RA, ankylosing spondylitis, peripheral vascular disease?), the safest bet is to answer cardiovascular cause (it is the MCC of death in general population too). Also note that chronic inflammatory conditions such as SLE and RA are associated with accelerated atherogenesis.

It is easier to remember only the exceptions to this rule, e.g., for scleroderma, the MCC of death is lung disease, and for primary biliary cirrhosis-liver failure, etc.

11.2 Joint Pathology

Inflammatory versus noninflammatory: Presence of any of the following suggests an inflammatory arthritis:

Morning stiffness >1 hour

¹ Inflammatory arthritis can present with joint stiffness alone without pain.

Joint stiffness lasting <1 hour can be due to the following: noninflammatory arthritis (e.g., osteoarthritis), nonerosive arthritis in SLE, or milder/early forms of inflammatory arthritis.
Red, hot joint
Elevated ESR (erythrocyte sedimentation rate) and/or CRP (C-reactive protein)

Acute versus chronic:

Acute (< 6 weeks)	Chronic (> 6 weeks)
Gout, pseudogout, and septic arthritis	RA, psoriatic arthritis, osteoarthritis, etc.

11.3 Rheumatoid Arthritis

Pathophysiology: In a patient with genetic susceptibility, an inciting factor (e.g., infection, smoking) leads to activation of autoimmune T-helper cells, causing joint inflammation.

Diagnosis: Made on clinical and lab findings, which include the following:

Inflammatory erosive arthritis involving three or more joints: arthritis is typically symmetric and commonly involves metacarpophalangeal and proximal interphalangeal joints.
Elevated ESR/CRP.
Positive serum RF (rheumatoid factor)

²Rheumatoid factor is autoimmune antibody against our own Immunoglobulin G (IgG). Immunoglobulin M (IgM) rheumatoid factor is commonly tested and is specifically helpful in assessing the course and prognosis. But note that negative serum rheumatoid factor does not rule out rheumatoid arthritis.
or anticyclic citrullinated peptide.
Extra-articular features are rheumatoid nodules, anemia of chronic inflammation, splenomegaly, amyloidosis, interstitial lung disease, etc.
Duration of symptoms for > 6 weeks
Debilitating joint deformities are common.

³Typical hand deformities in rheumatoid arthritis.

Management: Initiate DMARD (disease-modifying antirheumatic drug) as soon as diagnosis is made. DMARDs slow the progression of disease.

Severity	Choice of DMARDs
Mild disease	Hydroxychloroquine or sulfasalazine
Moderate to severe disease	Methotrexate

As DMARDs take some time to work, we can use nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids for immediate symptomatic relief (bridging therapy).

Side effects of common DMARDs

DMARD	Side effect
Methotrexate	Hepatotoxicity and liver cirrhosis (with long-term use) Megaloblastic anemia: use leucovorin or folic acid to prevent this.	In patients taking methotrexate, follow CBC (complete blood count) and LFTs (liver function tests) regularly.
Methotrexate	Pulmonary fibrosis Stomatitis (mouth ulcers and pain)
Azathioprine	Pancreatitis Hepatotoxicity Bone marrow suppression
TNF antagonist (etanercept, infliximab, adalimumab)	Can cause reactivation of tuberculosis, so do PPD (purified protein derivative) test before starting treatment
Hydroxychloroquine	Cinchonism (gastrointestinal and visual disturbances) In patients taking this for long-term, perform regular eye exam
Sulfasalazine	Side effects are similar to sulfonamides and penicillin (rash, hemolysis, Stevens-Johnson syndrome, etc.)Additionally, can cause drug-induced lupus

MRS

Anti-TNF agents are INFliximab (MAB = monoclonal antibody to TNF), eTaNeRCept (TNF Receptor antagonist), etc.

Disease associations

Rheumatoid arthritis	Dx
+ Lung problem (pneumoconiosis)	Caplan’s syndrome
+ Neutropenia + splenomegaly	Felty’s syndrome
+ Heart problem or kidney problem	Secondary amyloidosis

Complications:

Atlanto-axial subluxation	Patients with hx of RA who need to undergo anesthesia and intubation should get a cervical spine X-ray. If found to have rheumatoid cervical spine involvement, patients need measures to stabilize spine before intubation, as they are at increased risk of Atlanto-axial subluxation. This can lead to anterior displacement of vertebral bone into the spinal canal causing acute spinal cord damage.
Increased risk of Baker’s cyst	This can form when inflamed synovium extends into the popliteal space. If it ruptures, it can present with swollen and tender calf (similar in presentation to deep venous thrombosis of calf).
Increased risk of osteoporosis	Screen with DEXA (dual-energy X-ray absorptiometry) scan regularly

11.3.1 Differential Diagnosis of Rheumatoid Arthritis

Parvovirus Infection in Adults

Risk factor: Frequent exposure to children (e.g., school teacher or day-care center worker).

Presentation: Recent-onset symmetrical polyarthralgia/arthritis with or without hx of classical rash (slapped cheek rash, or lacy rash that looks a like a fish net). It may be confused with RA due to symmetric inflammatory arthritis. Look for acute onset and history of contact with children.

Diagnosis: Check antiparvovirus IgM in immunocompetent patients. In immunosuppressed individuals, check viral polymerized chain reaction (PCR), as they are less likely to mount an antibody response.

Treatment: NSAIDs. It is usually a self-limiting condition.

Complication: Aplastic crisis or chronic pure red cell aplasia can occur in patients with hematologic disorder or who are immunosuppressed. Primary infection during pregnancy can lead to intrauterine fetal death and/or hydrops fetalis (due to severe fetal anemia).

Juvenile Rheumatoid or Idiopathic Arthritis (JRA aka JIA)

Pathology: Autoimmune joint inflammation. The difference between JRA and RA is that many people with JRA outgrow their disease, whereas RA is usually a lifelong disease.

Presentation: Can initially present with indolent isolated hip pain and progress on to polyarticular symmetric arthritis. Joint disease can progress rapidly.

Dx: Made clinically with the help of inflammatory markers such as elevated ESR, ferritin, and autoimmune markers.

Serology in JRA
Positive ANA	May not be related with disease severity, but does signal increased risk of uveitis
Positive RF	May signal poor prognosis and increased chances of having disease into their adulthood

Management: NSAIDs + DMARDs (except in patients with low-disease activity). All patients are recommended to have periodic slit lamp examination, as coexistent asymptomatic iridocyclitis can lead to blindness, if left untreated.

Systemic-Onset Juvenile Idiopathic Arthritis (Formerly Known as Systemic JRA or Juvenile-Onset Form of Still’s Disease

⁴ Even though rare, adult-onset Still’s disease can occur.
)

Background: Idiopathic inflammatory condition that rarely occurs in patients older than 35 years. It is a subtype of JRA with prominent extra-articular manifestations.

Clinical dx:

History of fever (intermittent high-spiking fevers for at least 2 weeks)
Arthritis
Salmon-pink maculopapular skin rash
Increased inflammatory markers such as leukocytosis, elevated ESR, ferritin, etc.
Patients may also have reticuloendothelial system involvement (tender cervical lymph nodes, splenomegaly, sore throat, etc.), and
Serositis (e.g., pericardial effusion, pleuritis).

MRS

Still too FAST

Still = Still’s disease
Too = 2 weeks of fever spikes
F = Fever
A = arthritis
S = Skin rash (salmon-red/pink colored), Splenomegaly, Serositis
T = Tender lymphadenopathy

Rx: (low yield)

Severity
Mild disease	NSAIDs
Severe disease, or not responding to NSAIDs	Anakinra OR canakinumab (these are IL-1 antagonists)

11.4 Sjogren’s Syndrome

Pathophysiology: Autoimmune destruction of salivary and lacrimal glands

Presentation:

Lacrimal gland involvement (known as keratoconjunctivitis sicca)	Burning and foreign-body sensation in eyes. Severe eye dryness can lead to corneal ulceration and scarring.
Salivary gland involvement	Results in difficulty in swallowing food (loss of salivary lubrication effect), dental caries (loss of protective effect of salivary secretions), and fissures in mucosa. Patients may have parotid gland enlargement.

Work-up: NSIDx is bedside Schirmer’s test (a filter paper is placed in the eye and the extent of wetness is measured). Check anti-Ro(SSA) and anti-La(SSB), which are specific serologic findings. Most specific test is salivary gland biopsy of lower lip, but may not be necessary.

Treatment: Maintain oral hygiene (avoid sugary drinks and drink water frequently to keep the mouth wet), and use artificial tears and/or saliva. Second-line agents are pilocarpine or cevimeline (these are procholinergic agents that promote glandular secretion).

Disease association: Other female-predominant autoimmune syndromes (e.g., RA, primary biliary cirrhosis).

Complication: Predisposes to malignant lymphomas. MC type is mucosa-associated lymphoid tissue (MALT) lymphoma, which commonly arises from salivary glands but can occur anywhere.

11.5 Systemic Lupus Erythematosus (SLE)

Description: SLE is an autoimmune disorder that can affect multiple systems.

Patients can present with any of the following:

	Additional info
Serositis	Inflammation of serosal membranes (e.g., pleurisy, pericarditis)
Oral ulcers	They are painless.
Arthritis	Migratory, symmetrical arthritis that is nonerosive.^a X-ray of joints is normal. (This is in contrast to RA, which is erosive, and X-ray is abnormal).
Photosensitivity	Sun exposure can cause flare-ups of malar or discoid rash.
Blood disorder	Anemia, leukopenia, and/or thrombocytopenia
Renal problems	Discussed in next page
ANA positive	Sensitive but not specific test
Immunological tests	Antiphospholipid, anti-Smith, and anti-dsDNA antibody may be positive.
Neurological disorder	Psychosis, seizures, cerebral vasculitis, etc.
Malar rash	Butterfly-shaped rash in the face
Discoid rash^b	This can cause scarring and atrophy	(a) Early lesion. (b) Late lesion with scarring. Source: Chronic Cutaneous Lupus Erythematosus. In: Sterry W, Paus R, Burgdorf W, eds. Thieme Clinical Companions-Dermatology. 1st ed. Thieme; 2006.
^aAdditional MRS I’M SANE even though I have SLE arthritis. SLE has Migratory, Symmetrical Arthritis that is Non-Erosive.
^bPresence of only discoid rash is called discoid lupus. Patients with discoid lupus can have positive ANA, but anti-dsDNA or anti-Smith antibody is usually negative.

MRS

SOAP BRAIN MD

Work-up: If patient has any of the features of “SOAP BRAIN MD,” NSIDx is serum ANA (which is the screening test). If ANA is positive, NSIDx is anti-Smith and anti-dsDNA antibodies (these antibodies are specific to SLE, but not sensitive).

11.5.1 Renal Involvement in SLE

SLE can cause nephrotic or nephritic syndrome.

Pathophysiology: Immune complexes (anti-dsDNA antibody and antigen complex) are deposited in the glomerulus with subsequent activation of complement pathway, hence anti-dsDNA titers usually correlate with the severity of renal disease. Patients with high anti-dsDNA titer and low complement levels most likely have severe renal disease.

⁵Also, anti-dsDNA titer and C3 levels are used to assess treatment response.

Work-up: In patients with SLE, always check urinalysis and serum creatinine to screen for renal involvement. UA may show RBC casts and/or proteinuria. If significant renal involvement is suspected, NSIM is renal biopsy.

11.5.2 Management of SLE

Mild disease	Antimalarials (hydroxychloroquine, chloroquine)
Moderate disease (nonorgan threatening)	Short-term prednisone + antimalarials
Severe disease (organ threatening, e.g., diffuse proliferative glomerulonephritis)	High-dose IV steroids + mycophenolate or cyclophosphamide^a
Skin disease	Topical steroids.Oral antimalarials if refractory or generalized disease
^a Side effects of cyclophosphamide Like any other antineoplastic agents, it can cause mucositis with gastrointestinal tract involvement (nausea, vomiting, diarrhea, stomatitis, etc.). Acute hemorrhagic cystitis: Mesna is co-administered to reduce risk. (Mesna inactivates the toxic component of cyclophosphamide in urine.) Increased risk of bladder cancer with chronic use.

11.5.3 Obstetric/Gynecological Issues Related with SLE

Combined oral-contraceptive pills are absolutely contraindicated in active SLE (can worsen disease) and in antiphospholipid syndrome (double trouble for the thrombotic state).
Screen all pregnant patients with SLE for SSA antibody (anti-Ro antibodies). These autoantibodies can cross the placenta causing neonatal lupus and congenital heart block.

⁶Anti-La (SSB antibody) cannot cross placenta.
In SLE patients with positive antiphospholipid antibody and history of prior fetal loss, use low-molecular-weight heparin and low-dose aspirin during pregnancy.

11.5.4 Drug-Induced Lupus

Etiology: It has been associated with the following drugs: Chlorpromazine (antipsychotic), Carbamazepine, Captopril, Hydralazine, Isoniazid, Methyldopa, Minocycline, Procainamide, Penicillamine, Phenytoin, Sulfasalazine, Sodium valproate, Quinidine, TNF inhibitors (e.g., infliximab, etanercept), Diltiazem, etc.

Presentation: Fever, arthralgia/arthritis, serositis, rash, pulmonary infiltrates, hepatospleno-megaly, etc.

Diagnosis: Specific test for drug-induced lupus is antihistone antibody. Presence of anti-dsDNA can occur with minocycline or TNF-inhibitor-induced disease. Low complement levels and kidney or CNS involvement are rare.

Management: Discontinue offending agent. Use NSAIDs for mild disease and steroids for severe disease. For persistent disease, start hydroxychloroquine.

MRS

cROSS A placenta:

Ro = anti-Ro antibodies;

SSA = SSA antibody.

MRS

CHIMP’S Queen Tonight Died of drug-induced SLE.

11.5.5 Other Causes of Migratory Arthralgia or Arthritis Besides SLE

Presentation: Joint pain (arthralgia) ± swelling and redness (arthritis) in different joints at different times. For example, CCS: patient presents with pain in the right knee joint. He also gives history of pain, swelling in the right wrist 3 days ago and left knee involvement 7 days ago.

Migratory arthralgia or arthritis + following findings	Likely Dx
Painless pustules (dermatitis)Pain and inflammation in tendons (tenosynovitis)± signs of septicemia	Disseminated gonococcal infection.Complication is gonococcal septic arthritis.
+ Fat malabsorption+ Skin pigmentation+ Generalized lymphadenopathy	Whipple disease
+ Hiking trip+ Hx of target-like rash+ Living in areas endemic for Lyme disease	Lyme disease
Recent hx of infection (diarrhea or urethritis)	Reactive arthritis due to Campylobacter jejuni or Chlamydia trachomatis infection
+ Hx of strep infection+ Carditis, chorea, subcutaneous nodules, or erythema marginatum	Rheumatic fever

11.6 Sclerosis (Scleroderma

⁷

• Localized to specific organs = CREST syndrome.

• Systemic involvement = systemic sclerosis.
)

11.6.1 Systemic Sclerosis (aka Systemic Scleroderma)

Background: An autoimmune disorder involving multiple organs in which normal tissues are replaced by fibrous tissues.

Organ affected by fibrosis	Clinical effect
Lung	Acute interstitial lung inflammation (indistinguishable from usual interstitial pneumonia) can be seen in earlier stages. Recurrent or persistent inflammation can lead to interstitial fibrosis (restrictive lung disease). The combination of pulmonary artery smooth muscle fibrosis and interstitial lung disease can lead to pulmonary hypertension (HTN) and cor pulmonale (MCC of death in scleroderma). NSIDx is high-resolution computed tomography (CT) scan.
Heart	Myocardial fibrosis, heart blocks
Subcutaneous tissue of skin	Skin thickening in face, trunk, hands, and fingers Some patients with systemic sclerosis may not have the skin findings (this is called systemic sclerosis sine scleroderma). This is why I think systemic sclerosis is a better name than scleroderma.
Esophagus and lower esophageal sphincter (LES)	Normal contracting smooth muscles are replaced by fibrous tissue, resulting in Acid reflux and peptic stricture (mechanical dysphagia), and/or Failure of LES to relax causing pseudoachalasia (nonmechanical dysphagia)
Small intestine	Fibrosis replaces intestinal smooth muscles causing stasis, which can lead to bacterial overgrowth and malabsorption.
Large intestine	Constipation and diverticulosis
Smooth muscles of renal vasculature	Scleroderma renal crisis: Abrupt-onset malignant HTN + acute renal failure ± microangiopathic hemolytic anemia.Rx: ACE (angiotensin-converting enzyme) inhibitor (drug of choice).
Patient also commonly have Raynaud phenomenon. Nail fold microscopy to look for underlying vascular changes helps in making the dx of systemic sclerosis.

Diagnosis: Made on clinical grounds and serology, as following:

Anti-Scl-70 antibody (anti-DNA topoisomerase antibody)

Anti-RNA polymerase III antibody

ANA with nucleolar pattern

Rx: Treatment is nonspecific and organ based. It also depends upon presence of ongoing inflammation. Commonly used drugs are immunosuppressants, such as methotrexate, steroids, hydroxychloroquine, etc.

MRS

Scl-70 = sclerosis in 70 organs = systemic diffuse sclerosis.

Anti-DNA (topoisomerase) and RNA (polymerase) antibodies occur in scleroDeRMA.

Both DNA and RNA are located chiefly in the nucleolus of nucleus. So, ANA is chiefly of nucleolar pattern.

11.6.2 CREST (Localized Form of Scleroderma)

Crest	Features
Calcinosis	Nodular swelling in the skin which can be painful or painless. X-ray will show subcutaneous calcification.
Raynaud phenomenon	See box below.
Esophageal involvement	Acid reflux and peptic stricture (mechanical dysphagia), and/orFailure of lower esophageal sphincter to relax causing pseudoachalasia (nonmechanical dysphagia)
Sclerodactyly	Thickening of skin folds in fingers or hands (sausage-shaped digits with very few wrinkles)	Source: Fever in autoimmune diseases. In: Siegenthaler W, ed. Siegenthaler’s Differential Diagnosis in Internal Medicine: From Symptom to Diagnosis. 1st ed. Thieme; 2007.
Telangiectasia	Dilated blood vessels on the face and neck

Diagnosis: Made with clinical picture and presence of serum anti-centromere antibody.

MRS

CREST = Centromere antibody.

Raynaud phenomenon

Background: Can be primary (isolated disorder) or secondary (associated with underlying autoimmune condition such as scleroderma, SLE, RA, dermato/poly-myositis, etc.).

Presentation: Triggers such as cold exposure or emotional upset may incite an episode which typically occurs in the following sequence:

Pallor and Pain (due to vasoconstriction) — Cyanosis (deoxygenation) — Redness (reactive vasodilation after ischemia).

Severe Raynaud can result in prolonged cyanosis, finger-tip necrosis, and ulcer.

Ulcers on the fingertips in severe Raynaud.

Source: Fever in autoimmune diseases. In: Siegenthaler W, ed. Siegenthaler’s Differential Diagnosis in Internal Medicine: From Symptom to Diagnosis. 1st ed. Thieme; 2007

Diagnosis: Nailfold microscopy is most commonly used for aiding in diagnosis (underlying vascular changes point toward underlying autoimmune disorder). NSIDx: check ANA.

Treatment: Try conservative measures first—avoid smoking and cold exposure (use gloves and wool stockings). If not responding, use nifedipine or amlodipine (decreases vasoconstriction).

MRS

PCR of Raynaud

11.6.3 Differentiating CREST and Scleroderma

• In CREST syndrome, skin involvement is localized to the face, hands, and forearm (i.e., acral distribution only). In systemic sclerosis, the skin involvement can involve the whole body including trunk and arms.
Any feature of CREST with additional involvement of any other organ, except isolated pulmonary HTN, is systemic sclerosis. Note: CREST can also be associated with pulmonary HTN (loud P2 sound on heart auscultation), but is usually not accompanied by pulmonary parenchymal fibrosis.

Nephrogenic systemic fibrosis

Gadolinium contrast (given with magnetic resonance imaging [MRI]) is almost exclusively excreted by kidney. If given to patients with advanced kidney disease, it can remain in tissues causing reactive fibrosis. Skin findings include patches, plaques, and peau d’orange appearance, along with sclerodactyly and other features similar to systemic scleroderma.

11.7 Dermatomyositis and Polymyositis

	Dermatomyositis		Polymyositis
Pathophysiology	Autoimmune inflammation of muscles
Presentation	Symmetrical proximal muscle weakness (e.g., difficulty climbing stairs, getting up from the chair, combing, carrying grocery bags) Patients can also have swallowing problems (oropharyngeal dysphagia, nasal regurgitation, and/or aspiration)
Differentiating features	Rash present		No rash
	Scaly, red or violaceous, papule or plaques on the dorsal surface of small hand joints (Gottron’s plaques) Source: Clinical features. In: Sterry W, Paus R, Burgdorf W, eds. Thieme Clinical Companions — Dermatology. 1st ed. Thieme; 2006.	Red or violaceous rash around eyes (aka heliotrope rash) and nose Source: Dermatomyositis. In: Laskaris G, ed. Color Atlas of Oral Diseases: Diagnosis and Treatment. 4th ed. Thieme; 2017.	No rash
	Could be paraneoplastic (associated with underlying malignancy)^a		Not associated with malignancy
Steps in Dx	First step: Muscle creatine kinase (CK) and enolase (both will be high). Additionally, check myositis-specific antibodies (e.g., anti-Jo-1 antibody^MRS-1).Second step: Electromyography (shows spontaneous fibrillation and decreased muscle potential).Third step: Muscle biopsy (most specific test).
Initial treatment to achieve remission	Oral corticosteroids as a bridging therapy with initiation of azathioprine, methotrexate, or mycophenolate at the same time when steroid is started.
After achieving disease remission	If patient remains stable, try to taper off steroids. If no flare-up after a slow steroid taper, can attempt to taper off immunosuppressant.
^aThink of the following conditions when muscle weakness is associated with malignancy: Myasthenia gravis: typically associated with thymoma which can be benign or malignant. Dermatomyositis: various malignancies. Lambert-Eaton: small-cell cancer.