Rheumatology

As discussed in the immunology section, the immune system is complex with many working parts. Sometimes, self-tolerance breaks down and the immune system attacks normal cells in the body. One of the main symptoms for these disorders is joint pain (arthralgias), thus they are placed in the realm of the rheumatologist, a physician who takes care of disorders related to joints. Below you will find a table of disorders and associated autoantibodies, a summary of common rheumatic disorders, and the medications used to treat them.

Disease Associated Markers
Rheumatoid Arthritis Anti-Cyclic Citrullinated Peptide (CCP)
Systemic Lupus Erythematosus (SLE) Anti-dsDNA
Anti-Smith
Drug-Induced Lupus Anti-Histone
Sjogren's Syndrome Anti-SSa (Anti-Ro)
Anti-SSb (Anti-La)
Granulomatosis with Polyangitis
Microscopic Polyangiitis
cANCA
pANCA
CREST syndrome Anti-centromere
Scleroderma Anti-Scl70
Polymyositis
Dermatomyositis
Anti-Jo1
Anti-Phosopholipid Syndrome Anti-Phosopholipid
Mixed Connective Tissue Disorder (MCTD) Anti-RiboNucleoProtein (RNP)
Ankylosing Spondylitis HLA-B27

Rheumatoid Arthritis (RA)

A Type-III hypersensitivity disorder of the joints characterized by joint erosion and extra-articular manifestations. It is more common in middle-aged women. The cause is unknown, though it is thought that pathogen destruction triggers autoimmune reaction against joint tissue. Patients present with morning stiffness lasting more than an hour and night pains that keep them up. Most commonly affected joints include PIP, McP, wrists, elbows, ankles, and knees; DIP and central joints are usually not affected. Fingers may show ulnar deviation, swan-neck and boutonniere deformities. Imaging will show inflammation of the joint (synovitis) which leads to permanent joint erosion. Labs may show positive rheumatoid factor (sensitive for RA) and anti-cyclic citrullinated peptide (specific for RA). Positive anti-dsDNA and anti-Smith are specific for SLE. Extra-articular manifestations include ocular disease, anemia, subcutaneous rheumatoid nodules, interstial lung disease, and vasculitis. Treatment involves DMARDs and TNFa inhibitors, which tend to work well. However, these inhibitors increase susceptibility to infection.

Juvenile Arthritis

The most common cause of arthritis in children, it is diagnosed by age, chronicity, and more than one affected joint. It can lead to permanent joint erosions and should be treated similarly to rheumatoid arthritis.

Seronegative Spondylitis

This is a group of disorders presenting with arthritis but lacking rheumatoid factor. It includes psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disorders, and Reiter's syndrome.

Ankylosing Spondylitis: The arthritis mainly affects the spine and sacroiliac joints, worsening at night but getting better with activity. Almost all patients have HLA-B27, but not all HLA-B27 individuals have ankylosing spondylitis. The disorder starts off as synovitis and enthesitis (inflammation of attachments to bone) of the joints, leading initially to bone destruction then bone production, fusing the joint. Patients may also present with anterior uveitis (ciliary body attachment), dactylitis (extensor sheath inflammation), aortitis, and decreased chest expansion. Imaging may show vertebral fusion (bamboo spine) or fusion in other joints. Treat with antiinflammatories as well as possibly surgery.

Psoriatic Arthritis (PA): An arthritis found in a percentage of patients with psoriasis, an autoimmune skin condition with scaly erythematous plaques. PA can cause dactylitis, enthesitis, and joint telescoping (pushing one bone into the other). Treat with antiinflammatories along with biologics.

Reactive Arthritis (Reiter's Syndrome): Caused by infection with either Chlamydia or an enteric infection. Patients present with arthritis, uveitis, and urethritis. Treat the infection, then treat the symptoms if they don't go away.

Systemic Lupus Erythematosus (SLE)

This is a Type II and III hypersensitivity disorder that can affect any tissue in the body, mainly affecting the skin, joints, kidneys, and serosa. It tends to affect both males and females equally until puberty, when females are disproportionately affected. Genetic and environmental influences result in immune complex deposition along with direct destruction of formed elements. UV exposure can increase symptoms, as well as certain medications. There are 11 diagnostic criteria, of which at least 4 are required: malar rash, discoid rash, photosensitivity, oral/nasopharyngeal ulcers, nonerosive arthritis, serositis, nephritis, cytopenia, neural symptoms (seizures and/or psychosis), ANA, and serology (presence of certain auto-antibodies). Other nondiagnostic features include Reynaud's, panniculitis, strokes (caused by pro-thrombotic state). Neonatal lupus, caused by transplacental exchange of anti-SSA and anti-SSB, presents most often with congenital heart block. Drug-induced lupus often presents with cutaneous symptoms and has positive anti-histone on serology; it is treated by removing the medication. Treatment includes the ones mentioned below, as well as sunscreen to prevent photosensitivity and ACE inhibitors to prevent worsening nephritis.

Scleroderma

A disorder caused by increased fibrosis of skin, blood vessels, and organs. Fibrosis is caused by cytokine production resulting in fibroblast proliferation and increased matrix production. Patients present with thickening and tightening of the skin, often on the hands and face. It can be divided into localized scleroderma, diffuse systemic scleroderma (DSSc), or limited systemic scleroderma (LSSc). LSSc is slow in onset, does not have renal involvement, is usually positive for anti-centromere, and has a better prognosis. CREST syndrome, found in a subset of LSSc patients, consists of: Calcinosis, Raynaud's, Esophageal, Sclerodactyly, and Telangiectasias. DSSc patients are affected on the limbs and trunk, have rapid progression, may be positive for anti-Scl70, and have a worse prognosis. Many DSSc patients are susceptible to sever acute hypertensive renal failure, which can cause death if untreated (treat with ACE inhibitor). Pulmonary fibrosis is also extremely common, leading to respiratory failure (leading cause of death).

Sjogren's Syndrome

A Type IV hypersensitivity disorder that damages moisture glands, it presents with the triad of dry eyes, dry mouth, and arthritis. Sicca symptoms refer to symptoms of dryness. It is thought that a pathogen damages ductal cells, exposing self-antigens which activate self-reactive B and T-cells. Signs of mouth dryness include parotid enlargement, dental caries, and oral candidiasis. Signs of eye dryness include a feeling of sand in the eye, eye fatigue, and itchiness. Other symptoms include vasculitis, neuropathy, and arthralgia/arthritis. Gland biopsy shows lymphocytic invasion and destruction of normal structures. Labs will usually be positive for Anti-SSA (anti-Ro) and Anti-SSB (Anti-La). Treatment involves eyedrops, cholinergics to stimulate saliva production, and antiinflammatories.

Polymyositis (PM) and Dermatomyositis (DM)

These inflammatory myopathies involve symmetrical weakness of proximal muscle groups, and require biopsy, muscle enzymes, and EMG findings, and cutaneous features for diagnosis. DM is caused by CD4 T-cells activating autoantibody production against perifascicular blood vessels. PM is caused by CD8 damage to the muscle fibers. Patients present with muscle weakness but normal reflexes and sensation. Patients may also have cardiomyopathy, respiratory muscle dysfunction, and restrictive lung disease. Skin is involved in DM (shawl sign, heliotrope rash) but not PM. Many patients are positive for anti-Jo1, directed against tRNA synthetase. Treatment is usually steroids with methotrexate.

Anti-Neutrophil Cytoplasmic Antibodies (ANCA)-positive Disorders

All of these disorders are small vessel vasculitides, causing fibrinoid necrosis. They often present with cutaneous as well as visceral symptoms.

p-ANCA: Also known as MPO-ANCA (myeloperoxidase). Found in microscopic polyangiitis and eosinophilic granulomatosis.

c-ANCA: Also known as proteinase 3-ANCA. Found in granulomatosis with polyangiitis. Presents with hemoptysis and hematuria, along with upper respiratory tract disorders.

Rheumatology Medications

General AntiInflammatories

Prednisone: Steroid used to decrease inflammation and immune system response. Has many transient and permanent side effects. Can cause thinning of skin, osteoporosis, hyperglycemia, hypertension, fat redistribution, and cataracts.

NSAIDs: Antiinflammatories that are distinguished from steroids (hence the name). They work by inhibiting COX-1 and COX-2 to different degrees, giving different effects and side effects. They enzymes are necessary to produce prostaglandins and thromboxane. Side effects include gastric ulcers, nephritis, and renal ischemia (prostaglandins normally dilate renal blood vessels).

Disease-Modifying Antirheumatic Drugs (DMARDs)

Methotrexate: A folate antagonist, inhibits purine synthesis, leading to inhibition of lymphocytes. May cause myelosuppression, pulmonary fibrosis, and liver damage.

Azathioprine: Inhibits purine synthesis, leading to inhibition of lymphocytes. May cause myelosuppression and liver toxicity.

Leflunomide: Inhibits pyrimidine synthesis, leading to inhibition of lymphocytes. May cause myelosuppression and liver toxicity.

Cyclophosphamide: An alkylating agent, inhibits lymphocytes. Causes hemorrhagic cystitis and transitional cell carcinoma.

Hydroxychloroquine An anti-malarial drug, it inhibits release of IL-1 and phospholipase to decrease inflammation. May cause eye toxicity.

Sulfasalazine Inhibits production of leukotrienes, also may inhibit TNF-a. Can cause nausea/vomiting/diarrhea, oligospermia, and Steven-Johnson Syndrome.

Biologics

Anti-TNFa Monoclonal Antibodies: These drugs are all monoclonal antibodies with different constant regions or different amounts of chimerism. Examples include infliximab, adalimumab, golimumab, and certolizumab.

Etanercept A soluble TNFa receptor, it binds to TNFa and prevents it from binding to receptors and activating inflammatory pathways.

Rituximab: A monoclonal antibody against CD20, inhibiting B-cell function.

Abatacept: A fusion molecule containing a CTLA-4 domain, it binds to T-cells, giving an inhibitory signal and preventing activation.

Anakinra: An IL-1 receptor antagonist, prevents IL-1 from binding and activating inflammatory pathways.

Tocilizumab A monoclonal antibody against the IL-6 receptor, prevents activation of inflammatory pathways.

Belimumab A monoclonal antibody against BLyS, preventing maturation of B-cells, leading to apoptosis.