The following sections outline potential drug toxicities to consider, as opposed to a primary rheumatic disease diagnosis.

Certain key medications or medication groups are elucidated with additional information to describe the clinical presentation and management approach for their respective drug-induced toxicity.

Drug-induced arthritis can be part of a more systemic disease (i.e., drug-induced lupus) or primary rheumatic disease (gout precipitation). 

Drug-Induced Arthropathies

  • Amphotericin B
  • Anti-mycobacterial:
    • Rifampicin
    • Rifabutin
  • Aromatase inhibitors (AI):
    • Anastrazole, letrozole, exemestane
    • Arthralgia 20-50%, arthritis up to 15%
    • 1-6 mos after starting AI, symmetrical small-large joints
    • Management: NSAIDs, duloxetine, treat vitamin D < 30ng/mL, switching AI may help, AI holiday then restart can help, low dose prednisone
    • Symptom resolution by ~4 wks of stopping AI
    • Prevention: concurrent therapy with anti-CDK4/6 (-ciclib) or bisphosphonates
  • Barbiturates
  • Beta blockers:
    • Metoprolol
  • Calcineurin inhibitor induced pain syndrome (CIPS)
  • DPP-4 inhibitors:
    • Sitagliptin, saxagliptin, linagliptin, alogliptin
    • Arthralgia 3-5%, arthritis 1%, 2015 black box warning for severe, debilitating joint pain
    • Symmetrical, polyarticular
      RF+ in 9%
    • Management: drug cessation, NSAIDs
    • Symptom improvement in 1-2 mos
  • Ethionamide
  • G-CSF:
    • Neupogen
    • Filgrastim
  • Herbal supplements
  • H2 receptor blockers (e.g., cimetidine)
  • Hydralazine
  • Immune checkpoint inhibitors (ICIs):
    • CTLA-4 inhibitors (ipilimumab, etc.), PD(L)1i (nivolumab, pembrolizumab, atezolizumab, etc.)
    • Arthralgia: 43%, arthritis: up to 10%, 4 mos – 2 yrs after ICI start even after ICI cessation
    • Presents as: symmetrical small joint, PMR-like, asymmetrical large joint
    • Can be seen with tendonitis, early erosions, colitis, psoriasis
  • NSAIDs, moderate dose steroids, may need DMARDs
  • Interferon alpha
  • Isoniazid
  • Oral contraceptives
  • Procainamide
  • Proton-pump inhibitors
  • Pyrazinamide
  • Quinidine
  • Quinolones (ciprofloxacin, levofloxacin)
  • Retinoids:
    • Isotretinoin, alitretinoin, acitretin, bexarotene
    • Back pain: 80%, other arthralgia: up to 30%.
      Inflammatory back pain: 25%, sacroiliitis on imaging: 5%
    • 2-6 mos after starting retinoid, sacroiliitis UL> BL, HLAb27+ in 15% of sacroiliitis
    • Management: retinoid discontinuation, NSAIDs
    • Symptom resolution and x-ray improvement: 1-12 mos
  • Taxanes:
    • Clitaxel
    • Docetaxel
    • Cabazitaxel
  • Tetracycline (minocycline, doxycycline)
  • Voriconazole
  • 5-HT2A antagonists:
    • Mianserin
    • Mirtazapine
    • Nefazodone

Drugs Associated with Gout Development

  • Diuretics
  • Radioactive phosphorus:
    • 32P
  • Aspirin (low doses)
  • Cytotoxic agents (used in leukemia therapy)
  • Nicotinic acid (large doses)
  • Pyrazinamide

Overview

  • Timing: typically months to years of exposure to the offending medication
  • Clinically: resembles primary systemic lupus erythematosus but less association with renal disease
  • Labs: antinuclear antibody and anti-histone antibody positivity is common 
    • Rarely positive SSA and dsDNA have been described (usually with the use of TNF alpha inhibitors) 
    • Hematologic abnormalities less frequent in drug-induced lupus
    • Hypocomplementemia is uncommon (except for quinidine-induced forms)

Subtypes of Drug-Induced Lupus

Systemic Lupus Erythematosus

Mild arthralgia, myalgia, serositis, and constitutional symptoms are common.

Subacute Cutaneous Lupus Erythematosus

Most common drug-induced lupus subtype.

  • Antiepileptics:
    • Carbamazepine
    • Phenytoin
  • Angiotensin-converting enzyme inhibitors
  • Calcium channel blockers 
  • Chemotherapeutic agents
  • Hydrochlorothiazide
  • Leflunomide
  • Proton-pump inhibitors 
  • Statins
  • Terbinafine
  • TNF-α inhibitors
Chronic Cutaneous Lupus Erythematosus
  • Rare but discoid lesions have been reported.
  • Fluorouracil compounds or their modern derivatives, such as capecitabine, have been associated with chronic cutaneous drug-induced lupus.

Treatment

  • Discontinuation of the offending agent
  • NSAIDs and low dose steroids may be helpful while waiting for symptoms to resolve, which typically occurs within 1-3 weeks.
  • If symptoms persist past 1 month, the condition has likely become chronic.

 

HMG-CoA Reductase Inhibitors (Statins)

  • Myalgia>myositis
  • Statins can unmask or worsen an underlying autoimmune myopathy.
  • Risk factor: lipophilic statins (simvastatin, atorvastatin, lovastatin) >>  hydrophilic counterparts (pravastatin, rosuvastatin, fluvastatin)
  • Management: consider switching to different statin

Immune Checkpoint Inhibitors (ICIs)

  • Prevalence <1%, but case- fatality rate >20%; risk factor: multiple ICIs
  • Onset: 1 wk to 6 mos
  • Proximal, symmetric weakness and pain
  • Monitor for concurrent myositis and/or myasthenia gravis
  • Biopsy: myofiber necrosis
  • Management: high dose immunosuppression determined by internal organ involvement and severity

Colchicine

  • Risk factor: higher doses, CYP P450 drug interactions, renal dysfunction
  • Muscle biopsy: necrosis and fibers with autophagic vacuoles

Corticosteroids

  • Risk factors: prolonged use, high doses
  • Usually with muscular atrophy
  • Typically does not cause an elevation in CK

Fibrates

  • Can produce a spectrum of manifestations that include asymptomatic serum creatine kinase elevation, myalgias, exercise-induced pain, rhabdomyolysis, and myoglobinuria

Other Meds

  • Amiodarone
  • Antimalarial drugs: very rare, can be with dysphagia, EM biopsy shows: myeloid and curvilinear bodies, management: stop antimalarial drug, may improve but usually not to baseline
  • D-penicillamine
  • Interferon alpha
  • Ipecac
  • Procainamide emetine
  • Vincristine

Toxins That Can Cause Myopathy

  • Alcohol, amphetamines, cocaine, heroin, phencyclidine, and meperidine
  • Can see widespread muscle breakdown, rhabdomyolysis, and myoglobinuria

Zidovudine (AZT) and Other Nucleoside Reverse Transcriptase Inhibitors

  • Months after med start
  • Risk factor: doses >600 mg/day
  • Mild CK elevation
  • Myopathic on EMG
  • Muscle biopsy: ragged red fibers, indicative of mitochondrial inclusions
  • Management: drug cessation
  • Prognosis: symptoms improve within 4 wks of holding the drug

Overview

  • Drug-induced vasculitis primarily involves small- and medium-sized blood vessels, and the clinical manifestations are like those of other idiopathic vasculitides. 
  • Almost any medication can be implicated in drug-induced vasculitis, and the clinical manifestations range from single organ involvement (most commonly, skin) to life-threatening multi-organ disease.
  • Clinical manifestations range from arthralgias to isolated cutaneous rashes to severe single or multi-organ involvement.
  • There are no unique pathologic or laboratory aspects of drug-induced vasculitis that differentiate it from other vasculitides.
  • Withdrawal of the offending agent is the most important step in management, but more severe cases may require immunosuppressive therapy.

Drug-Associated Vasculitides Classified by Vessel Size Involvement

Below are commonly reported drug-associated vasculitides classified by vessel size involvement.

Large Vessel Drug-Induced Vasculitis 

Type of vasculitis that affects the aorta and its major branches

  • Granulocyte colony-stimulating factor (aortitis)
  • Immune checkpoint inhibitors (aortitis)
  • Amphetamines (cerebral vasculitis)
  • Cocaine (cerebral vasculitis)
Medium Vessel Drug-Induced Vasculitis

Vasculitis that predominantly affects the medium arteries, such as the main visceral arteries and their branches

Small Vessel Drug-Induced Vasculitis

Type of vasculitis that predominantly affects intraparenchymal arteries, arterioles, capillaries, and venules

a. ANCA-Associated Vasculitis
Typically associated with an atypical ANCA or MPO-ANCA, but antibodies against elastase and lactoferrin are commonly reported. End-organ damage, including necrotizing glomerulonephritis and alveolar hemorrhage, are less frequent.

  • Allopurinol
  • Cocaine contaminated with levamisole
  • D-penicillamine
  • Hydralazine
  • Immune checkpoint inhibitors
  • Isoniazid
  • Methimazole
  • Phenytoin
  • Propylthiouracil
  • Sulfasalazine
  • TNF-inhibitors

b. IgA Vasculitis 
Immune complex-mediated, small vessel vasculitis with IgA1-dominant immune deposits

  • Antibiotics
  • Furosemide
  • NSAIDs
  • Statins
  • TNF-inhibitors
  • Warfarin

c. Leukocytoclastic Vasculitis
Onset of skin rash within 1–3 wks after drug initiation

  • Allopurinol
  • Amiodarone
  • Antibiotics
  • Anti-tuberculosis drugs
  • Immune checkpoint inhibitors
  • NSAIDs
  • Sulfonamides
  • TNF-inhibitors
  • Valproic acid
  • Warfarin
  • Zidovudine (AZT) and didanosine (hypersensitivity angiitis)

d. Peripheral Vasculitic Neuropathy
Clinical presentation includes mononeuropathy, mononeuritis multiplex, or sensorimotor polyneuropathy

Overview

  • Serum sickness is an immune complex-mediated reaction to injections of foreign serum or protein that occurs 1 to 2 weeks after exposure or sooner if there has been a previous exposure.
  • Serum sickness-like reaction presents clinically very similarly to serum sickness, but does not involve the formation of immune complexes.
  • Manifests as fever, rash, joint pain, and joint swelling in a symmetrical distribution
  • May occur with many medications, but penicillin is a common cause.
  • Meds that can cause serum sickness or serum sickness-like reactions:
    • Anti-venom injections (for venomous snake bites, etc.)
    • Antibiotics: penicillins, sulfonamides
    • Anti-epileptics: phenytoin, carbamazepine
    • Rheum drugs: allopurinol, rituximab, infliximab
  • Infections like streptococcus and hepatitis B can cause serum-sickness like reactions.

Treatment