6.10 Other Primary Rheumatic Disorders & Mixed Connective Tissue Disease

1. Adult-Onset Still Disease

A systemic autoinflammatory disorder and a classic cause of fever of unknown origin in a young adult. The triad worth memorizing:

1. Quotidian fever — a daily spike, typically in the late afternoon or evening, returning to normal between spikes
2. Evanescent salmon-colored macular rash — appears with the fever spike and vanishes as it defervesces, so it is frequently absent when the patient is examined in the morning
3. Arthralgia or arthritis, plus sore throat, which is characteristic and often overlooked

Laboratory profile: marked leukocytosis with neutrophil predominance, elevated inflammatory markers, elevated aminotransferases, and a strikingly elevated ferritin — often over 1,000 and sometimes over 10,000 ng/mL. A low glycosylated ferritin fraction adds specificity. Rheumatoid factor and antinuclear antibody are characteristically negative, which is what separates it from rheumatoid arthritis and lupus.

It is a diagnosis of exclusion: infection, malignancy (especially lymphoma) and other autoimmune disease must be ruled out. Treatment ranges from NSAIDs through corticosteroids to interleukin-1 and interleukin-6 inhibition. The most feared complication is macrophage activation syndrome, signaled by a falling white count and platelet count with a rising ferritin and triglycerides in a previously inflamed patient.

2. Behcet Disease

A variable-vessel vasculitis most prevalent along the historic Silk Road — Turkey, the Middle East, Central and East Asia.

Cardinal features:

• Recurrent oral aphthous ulcers — required for diagnosis, typically at least three episodes per year
• Genital ulcers, which scar
• Ocular disease — uveitis, classically posterior uveitis or panuveitis, and hypopyon; a leading cause of blindness
• Skin lesions — erythema nodosum, pseudofolliculitis, acneiform nodules
• Pathergy — a papule or pustule forming at a needle-prick site after 48 hours

Distinctive complications include venous thrombosis (treated with immunosuppression rather than anticoagulation alone), pulmonary artery aneurysm — a rare cause of hemoptysis in which anticoagulation is dangerous — and neuro-Behcet disease.

3. Relapsing Polychondritis

Immune-mediated inflammation of cartilage. The examination pearl is anatomic: auricular chondritis spares the earlobe, because the lobe contains no cartilage. A red, swollen, tender pinna with a normal lobe is nearly diagnostic.

Other features: saddle-nose deformity from nasal cartilage collapse, laryngotracheal involvement producing hoarseness, stridor and potentially life-threatening airway collapse, costochondritis, audiovestibular dysfunction, non-erosive arthritis, and aortic root dilation.

Airway involvement is what makes this dangerous and is the reason it cannot be managed as a purely cosmetic problem. It is associated with myelodysplastic syndrome in older patients, and treatment is corticosteroids with steroid-sparing immunosuppression.

4. Fibromyalgia

A disorder of central pain processing — not an inflammatory or autoimmune disease. Widespread pain of at least three months, with fatigue, unrefreshing sleep and cognitive difficulty (fibro fog). Inflammatory markers, complete blood count and imaging are normal; abnormal results point to another diagnosis.

Management is heavily tested and counterintuitive: the intervention with the best evidence is graded aerobic exercise, alongside cognitive behavioral therapy and sleep hygiene. Pharmacotherapy is adjunctive — duloxetine, milnacipran, pregabalin or low-dose amitriptyline. Opioids and corticosteroids are ineffective and harmful. Coexisting fibromyalgia in a patient with rheumatoid arthritis or lupus explains persistent pain despite controlled inflammation, and the correct response is not to escalate immunosuppression.

5. Sjogren Syndrome

Lymphocytic infiltration of exocrine glands producing keratoconjunctivitis sicca and xerostomia. Diagnosis uses anti-Ro (SSA) and anti-La (SSB) antibodies, objective testing of tear production (Schirmer test) and salivary flow, and minor salivary gland biopsy when serology is negative.

Extraglandular disease includes interstitial lung disease, renal tubular acidosis (distal, type 1), small-fiber neuropathy and cutaneous vasculitis.

Two facts that dominate exam items:

• Markedly increased risk of non-Hodgkin lymphoma, particularly MALT lymphoma. Persistent unilateral parotid enlargement, new lymphadenopathy, a falling complement C4 or a new monoclonal gammopathy warrants evaluation for lymphoma.
• Anti-Ro crosses the placenta and causes congenital heart block and neonatal lupus; pregnant patients require fetal monitoring.

6. Mixed Connective Tissue Disease

A separately enumerated blueprint subsection. Defined by a high-titer anti-U1 ribonucleoprotein (anti-RNP) antibody together with overlapping features of lupus, systemic sclerosis and inflammatory myositis.

Characteristic combination:

• Raynaud phenomenon — nearly universal and usually the first symptom
• Swollen sausage-like fingers (puffy hands) — a highly characteristic early sign
• Arthritis, often more erosive than in lupus
• Myositis with proximal weakness and elevated creatine kinase
• Esophageal dysmotility
• Pulmonary arterial hypertension — the leading cause of death, in contrast to lupus where renal and infectious causes dominate

Severe lupus nephritis and severe central nervous system disease are comparatively uncommon. Because pulmonary hypertension drives mortality, periodic echocardiographic screening is part of routine care. Over time, some patients evolve into a defined connective tissue disease.

Undifferentiated connective tissue disease describes patients with autoimmune features and autoantibodies who do not meet criteria for any specific disease; a substantial proportion never progress.

7. Marfan and Ehlers-Danlos Syndromes

Marfan syndrome — autosomal dominant FBN1 mutation affecting fibrillin-1.

Management centers on serial echocardiographic surveillance of the aortic root, beta-blockade or angiotensin receptor blockade to slow dilation, prophylactic aortic root replacement at a size threshold, and avoidance of isometric and contact sport. Pregnancy carries substantial dissection risk and requires pre-conception aortic assessment.

Ehlers-Danlos syndromes are a heterogeneous group with joint hypermobility, skin hyperextensibility and tissue fragility. The subtype that matters most is vascular Ehlers-Danlos syndrome (type IV), caused by COL3A1 mutation, which produces spontaneous arterial, bowel and uterine rupture with thin translucent skin and easy bruising. It carries markedly reduced life expectancy, and arteriography and elective vascular procedures are hazardous because the vessels tear.

Contrast for the exam: lens dislocation is superotemporal in Marfan syndrome and inferonasal in homocystinuria; homocystinuria is autosomal recessive, causes intellectual disability and thrombosis, and is screened for biochemically.

8. Charcot-Marie-Tooth Disease

A separately named blueprint subsection despite being a hereditary neuropathy. The most common inherited peripheral neuropathy, usually autosomal dominant, commonly from PMP22 duplication.

Clinical signature:

• Distal, length-dependent weakness and atrophy beginning in the feet — the classic inverted champagne bottle appearance of the legs
• Pes cavus and hammer toes, often the presenting complaint and a strong clue to a long-standing hereditary process
• Foot drop with a steppage gait
• Absent ankle reflexes; comparatively mild sensory complaints
• Slowly progressive over decades, with a positive family history

Demyelinating forms show uniformly slowed conduction velocities on nerve conduction studies; axonal forms show reduced amplitudes. Diagnosis is confirmed genetically. There is no disease-modifying therapy; management is bracing, physical therapy and orthopedic care. Neurotoxic drugs — vincristine in particular — must be avoided, since they can precipitate severe, irreversible deterioration.

9. Arthropathy of Hemochromatosis and Scoliosis

Hemochromatosis arthropathy classically affects the second and third metacarpophalangeal joints — an unusual distribution that should prompt iron studies. It resembles osteoarthritis radiographically with hook-like osteophytes, is frequently associated with chondrocalcinosis and calcium pyrophosphate deposition, and characteristically does not improve with phlebotomy even when systemic iron overload is corrected.

Scoliosis in adults matters when the Cobb angle is large enough to produce restrictive lung disease and, in extreme cases, chronic hypercapnia and cor pulmonale.

10. Juvenile Idiopathic Arthritis in the Adult Clinic

Juvenile rheumatoid arthritis is explicitly enumerated in this blueprint subsection, and it appears on an internal medicine examination because these patients survive into adulthood and transfer to adult care, often with sequelae that a clinician unfamiliar with the diagnosis will misread.

The adult presentation of a childhood-onset disease:

• Persistent disease activity in adulthood in a substantial proportion, requiring ongoing disease-modifying therapy rather than the assumption that the illness burned out
• Growth abnormalities — micrognathia from temporomandibular joint involvement, leg-length discrepancy, and short stature from chronic inflammation and corticosteroid exposure
• Joint damage and early secondary osteoarthritis, frequently requiring arthroplasty at a young age
• Cervical spine involvement with apophyseal fusion and atlantoaxial instability — a specific anesthetic hazard that must be assessed before any intubation
• Chronic anterior uveitis, which in the oligoarticular ANA-positive subtype is insidious and asymptomatic, causing cataract, synechiae, band keratopathy and blindness if surveillance lapses. Slit-lamp screening obligations continue into adulthood.
• Osteoporosis from disease activity, corticosteroids and reduced peak bone mass

Systemic juvenile idiopathic arthritis is the childhood counterpart of adult-onset Still disease and shares its features — quotidian fever, evanescent salmon-colored rash, serositis, marked ferritin elevation — and its risk of macrophage activation syndrome.

The practical points for the internist: confirm the specific subtype and past therapy at transition, maintain ophthalmologic surveillance, evaluate the cervical spine before procedures requiring airway manipulation, address bone health and cardiovascular risk, and do not discontinue disease-modifying therapy on the assumption that a pediatric disease has resolved.