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 Table of Contents  
Year : 2019  |  Volume : 14  |  Issue : 5  |  Page : 82-89

Drug-Induced Musculoskeletal Syndromes and Soft-Tissue Rheumatism

Department of Rheumatology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India

Date of Web Publication2-Dec-2019

Correspondence Address:
Dr. Parasar Ghosh
Department of Rheumatology, Institute of Post-graduate Medical Education and Research, Kolkata, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.272160

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Drug-induced musculoskeletal syndromes represent a broad clinical spectrum, ranging from asymptomatic biological abnormalities to severe organ-threatening manifestations. Many drugs have been implicated in inducing rheumatological adverse events. For some compounds, there is pathological or epidemiological evidence for a causal link, and for others, the association is based on anecdotal reports. Several different types of musculoskeletal symptoms occur ranging from chondropathy to arthritis to periarticular symptoms. The most common afflictions are hyperuricemia and gout arising from a variety of commonly used medications such as antitubercular drugs, diuretics, and low-dose aspirin. Although virtually all drug classes may induce some form of musculoskeletal disorders, a significant chunk is corticosteroids, especially injectable, antibiotics, lipid-lowering agents, and newer generation antidiabetics. Knowledge of drug-induced musculoskeletal disorders avoids burdening the patient with an array of unnecessary investigations and allows optimal management of the patients, which includes early discontinuation of the offending agent.

Keywords: Chondropathy, corticosteroid crystal-induced synovitis, gout, periarthritis, tendon rupture

How to cite this article:
Goswami RP, Ghosh P. Drug-Induced Musculoskeletal Syndromes and Soft-Tissue Rheumatism. Indian J Rheumatol 2019;14, Suppl S1:82-9

How to cite this URL:
Goswami RP, Ghosh P. Drug-Induced Musculoskeletal Syndromes and Soft-Tissue Rheumatism. Indian J Rheumatol [serial online] 2019 [cited 2022 Aug 12];14, Suppl S1:82-9. Available from:

  Introduction Top

Drug-induced musculoskeletal disorder is a wide-ranging clinical spectrum, from asymptomatic abnormal reports to severe and sometimes life-threatening or organ threatening manifestations. Majority of such reactions are benign arthralgias and myalgias. However, the severity of such reactions is unpredictable, varying from patient to patient and brands to brands, for any given molecule, and is often dependent on the dose of the drug, the duration of exposure, and the genetic predisposition of the host.[1]

A vast array of drugs has been linked to various rheumatological syndromes. Some of these have pharmacological basis and others have epidemiological associations. Some of the other associations are purely anecdotal available from case reports or series.[1] Early recognition is important because it avoids further confusion and unnecessary investigations. An iatrogenic origin should always be kept in mind.[1],[2],[3],[4],[5]

After excluding drug-induced bone disorders, lupus, vasculitis, and myositis, drug-induced musculoskeletal symptoms and soft-tissue rheumatism can be broadly classified into chondropathy, inflammatory arthritides, and periarticular disorders. Although arthritis is not part of soft-tissue rheumatism, we have included intra-articular corticosteroid (IACS)-induced arthritis as it is possibly the most common iatrogenic arthritis we see in our daily clinical practice.

  Search Strategy Top

We searched PubMed (including MEDLINE and PubMed Central) on September 10, 2019, using the search term “Drug Induced Rheumatism” and retrieved 12477 results. We limited our search to articles published in the past 5 years. Our search resulted in 2617 articles. The titles and abstracts of these articles were manually screened to identify observational studies, case series, and case reports. Other articles of relevance to the study topic were included based on the authors' personal knowledge and cross-referencing.

  Drug-Induced Chondropathy Top


Experimental evidence shows that both first-generation quinolones (nalidixic acid) and later-generation fluoroquinolones can be implicated in cartilage lesions.[6] In humans, there are several reports of lower extremity arthropathy after quinolone use in patients with cystic fibrosis. Joint symptoms occur within 2 weeks of therapy.[2] The symptoms are usually joint pain and myalgia, but arthritis with joint effusions may also occur rarely.[3] These resolve, without stigmata, after drug withdrawal, within 2 weeks to 2 months.[2],[3],[6]

A low incidence of 1.5% was reported from a large retrospective cohort of 1795 children on treatment with ciprofloxacin, and all were reversible.[7] Magnetic resonance imaging fails to show cartilage damage in children receiving ciprofloxacin for up to 3 months.[5],[8]

Intra-articular corticosteroids

It is said that IACS may accelerate joint damage from their catabolic effects.[9] Several cases of rapid joint destruction resulting in Charcot-like arthropathy are reported after repeated injections in the same joint.[2],[5] There is some concern that mixing lidocaine with corticosteroid may accelerate steroid crystal precipitation and subsequent arthritis. However, anecdotal evidence is against this.

In a randomized, double-blind trial, 68 patients with knee osteoarthritis were treated with IACS versus saline every 3 monthly for up to 2 years.[10] Joint space measurements at the end of the study did not show any progression of disease differentially between the two groups. Thus, judicious use of IACS (≤4 injections/joint/year and the interval between two injections in the same joint being kept at least 3 months) has a low risk of joint damage.[5],[10] On the other hand, there is no evidence to suggest that IACS prevents cartilage degradation.[5],[10]

  Inflammatory Arthritis Top

Crystal-induced arthritis: Gout

A vast array of drugs has been implicated in causing hyperuricemia. A partial list of drugs with their mechanism is available in [Table 1].
Table 1: Mechanisms and examples of drugs causing hyperuricemia

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Diuretics are perhaps the most commonly used agents to treat hypertension and congestive heart failure, and the association of hyperuricemia with its use has been long appreciated.[11],[12] The risk of gout with diuretic use is as high as 3- to 20-fold.[13] Pathogenic mechanisms are multifactorial including sodium wasting, volume depletion, and reduced fractional excretion of urate causing urate retention.[14] However, this is a partial explanation at best, and individual agents may have individual effects. For example, loop diuretics interact with NPT4 (a tubular urate transporter),[15] and both thiazide and loop diuretics inhibit MRP4 (a renal urate exporter).[16] Not all diuretics cause hyperuricemia. The potassium-sparing ones such as triamterene, amiloride, and spironolactone are not implicated in hyperuricemia. Tienilic acid is an interesting case. This was one diuretic that actually would increase renal urate excretion even if they induced volume depletion. However, it was withdrawn as a result of hepatotoxicity. While some advocate urate-lowering therapy for extreme hyperuricemia (<10 mg/dL), others are against this practice if renal function is normal.[5],[17],[18]

Posttransplant is another setting where hyperuricemia and infrequently gout are seen. The offending drugs are cyclosporine or tacrolimus other than diuretics. However, the etiology is multifactorial with contributions from renal failure, male gender, old age, obesity, and concomitant diuretic use.[2],[4],[19],[20],[21],[22] An incidence rate of 7.6% of new-onset gout was reported in an US survey postrenal transplant.[21] Patients on rather than tacrolimus were more likely to develop gout. Cyclosporine causes tubulointerstitial injury and arteriolar hyalinosis. On the other hand, hyperuricemia exacerbates the nephrotoxicity of cyclosporine.[23],[24]

The third important group contains weak organic acids. They raise serum urate by virtue of their action at the level of URAT1 (urate transporter) and OAT10 (organic anioninc transporter) (both tubular epithelial cell urate reabsorbing transporters). These drugs may also inhibit tubular secretion by acting as competitors to urate. Prominent examples are nicotinic acid and low-dose aspirin. Nicotinic acid additionally also promotes urate formation.[25] At low doses, aspirin causes hyperuricemia by inhibiting urate efflux. At high doses, aspirin becomes uricosuric apparently through the inhibition of URAT1.[15],[26]

The fourth important group is antitubercular drugs, namely ethambutol and pyrazinamide, both of which are core drugs against tuberculosis, and both induce hyperuricemia, especially pyrazinamide.[2] Interestingly, pyrazinamide may also induce arthralgia unrelated to hyperuricemia.[2],[4] Pyrazinamide is the strongest urate-retaining drug.[25] Pyrazinamide is metabolized to pyrazinoate and later to 5-hydroxypyrazinoate,[26] which are weak organic anions, and the mechanism of hyperuricemia is similar to low-dose aspirin or nicotinic acid.

Finally, there are many other offending drugs, and virtually, the list is endless. Of note are beta-blockers in contrast to calcium channel blockers which actually modestly reduce uric acid levels, Vitamins B1 and B12, commonly prescribed H2 receptor antagonists, and proton-pump inhibitors.[2],[5]

Intra-articular corticosteroids

IACS injections cause a localized inflammatory response in <5% of patients.[5] The onset is generally within hours and subsides without any long-term consequence within a few days. Treatment is generally reassurance, ice compression, and oral pain medications. The cause is corticosteroid crystal formation and precipitation and synovitis[2],[4],[5],[9] and occurs more frequently with poorly soluble needle-shaped triamcinolone hexacetonide injections. Arthrocentesis may become necessary to exclude infections. However, it is useful to remember that after a safely and aseptically performed intra-articular injection, probability of such infection is miniscule (about 1 case per 14 000–50 000 procedures).[5],[6]


Anecdotal evidence of drug-induced arthritis and arthralgia are numerous and available through many case reports and some series. However, associations are neither strong nor consistent for most reported incidences. Some require special mention apart from those well-documented cases of drug-induced lupus or vasculitis.


One example is definitely bisphosphonates. After an infusion of nitrogen-containing bisphosphonate, many patients very commonly report a flu-like syndrome.[27],[28],[29],[30],[31],[32] This is characterized by fatigue, malaise, myalgia, arthralgias to arthritis, and leukopenia. During this episode, macrophages and osteoclasts are sensitized and activated, releasing a number of cytokines chiefly tumor necrosis factor-α, interleukins 1 and 6, resulting in inflammation and rise of C-reactive protein (CRP) and serum amyloid protein.[33] The magnitude of immune activity after a bisphosphonate infusion varies from molecule to molecule. While both pamidronate and zoledronate induce interleukin-6 (IL-6), ibandronate fails to do so,[34],[35],[36] and all three induce tumor necrosis factor-alpha.[32] Both pamidronate and zoledronate increase CRP levels,[29],[33] but ibandronate typically fails to do so.[34] Pamidronate also induces the acute phase protein elastase.[37] Pamidronate, ibandronate, and zoledronate all induce γδ+T cells.[38],[39],[40],[41]

The transient flu-like symptoms associated with intravenous bisphosphonates usually linger <72 h and occur primarily in naïve patients, and a recurrence is rare.[27],[28],[29],[30],[31],[32] Fever occurs often with malaise and myalgia, and the cited incidence is as high as 30%–55%.[31] Nonaminobisphosphonates and oral bisphosphonates do not cause this. Studies on pamidronate and zoledronate reported fever in 16%–30% of patients[29],[33],[34],[35],[37],[42] and in 0%–11% of patients treated with ibandronate.[29],[34],[36],[37] In a clinical trial comparing ibandronate to pamidronate for the treatment of hypercalcemia of malignancy, ibandronate caused fewer flu-like symptoms.[43]

Iron chelator

Transient joint pain, joint swelling, and myalgia or soreness occur in 15%–30% of patients with infusion of the deferiprone.[44],[45] However, underlying thalassemic arthropathy may both be worsened and improved by iron chelation therapy.[44]

Dipeptidyl peptidase-4 inhibitor and glucagon-like peptide-1 analog

Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are used in type 2 diabetes mellitus (T2DM) for better glycemic control and are a new addition to the armamentarium against diabetes.[46],[47] In 2014, Crickx et al.[48] reported three middle-aged persons with T2DM treated with gliptins (vildagliptin in 1 and sitagliptin in 2) who developed bilaterally symmetric polyarthralgia involving knees, ankles, and wrists in two patients and synovitis of the metacarpophalangeal joints and proximal interphalangeal joints of the hands in two. Time to development of articular symptoms varied from 2 months to 1 year. Joint radiographs were normal, i.e., arthritis was nonerosive in two, and rheumatoid factor and anticyclic citrullinated peptide (CCP) antibodies were negative in all three. Two patients improved within 1 month of drug discontinuation. However, the third affected woman had positive antinuclear antibodies and anticentromere antibodies, but rheumatoid factor and anti-CCP antibodies were negative. She was later diagnosed to have Sjogren's syndrome, did not respond to glucocorticoids and methotrexate and eventually responded to sitagliptin withdrawal, and could be weaned off methotrexate and steroids within 1 month. Later, a similar case was reported on a patient receiving liraglutide, a glucagon-like peptide 1 analog, another new antidiabetic drug.[49] After 9 months of treatment with liraglutide, the patient reported symmetric small and large joint arthralgias and puffy fingers. X-rays failed to show any erosion. Magnetic resonance imaging of the hips showed effusion and again no erosions. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were raised, but rheumatoid factor, anticyclic citrullinated protein antibody, and antinuclear antibodies were negative. The patient was treated with 30 mg/day deflazacort, but symptoms persisted. However, it improved within 1 week of liraglutide withdrawal. There exists controversy with regard to this topic since a cohort study of >73,000 patients with T2DM from the United States of America revealed that the use of DPP-4 inhibitors actually decreased the risk of incident autoimmune diseases, including rheumatoid arthritis.[49]

The United States Food and Drug Administration (FDA) Adverse Event Reporting System database reported 33 cases of severe joint symptoms linked to DPP-4 inhibitors used from October 16, 2001 (date of approval), to December 31, 2013.[50] The most commonly reported DPP-4 inhibitor was sitagliptin (n = 28), saxagliptin (n = 5), linagliptin (n = 2), vildagliptin (n = 2), and alogliptin (n = 1). At all events, joint symptoms were severe and disabling. The offending drug was discontinued within the month in 20 cases, and in others, the drugs were continued for up to 1 year. In majority, symptoms completely resolved within 1 month. In 8 patients, symptoms reappeared with rechallenge. After this report, the FDA issued a safety announcement related to the entire drug class and alerted physicians.[51] It should be noted that DPP-4 has recently been identified as a marker of activated fibroblasts and it might be one of the factors implicated in the regulation of transforming growth factor-beta-induced fibroblast activation. Inhibition of DPP-4 exerted potent antifibrotic effects in well-tolerated doses and is being investigated as a potential drug target in scleroderma.[52]

  Periarticular Disorders Top


Toxic tendinopathy has been linked conclusively to the following drug classes: fluoroquinolone antibiotics, systemic corticosteroids, statins, and aromatase inhibitors.[53],[54]

The first cases of quinolone tendinopathy were reported in the 1980s, nearly two decades after the introduction of the drug class.[55] The incidence is unknown but is estimated to be rare (range: 0.14%–0.4%).[56] A nested case–control study from the UK general practice database showed a rather high overall risk of Achilles tendon pathologies related to quinolones (3.2 cases/1000 patient-years).[57] Among the elderly, 2%–6% of all Achilles tendon ruptures can be attributed to quinolones.[58] Additional risk factors attributed to fluoroquinolone tendinopathy are concomitant use of corticosteroids and renal failure.[56],[57],[58] Other risk factors are renal failure, renal transplantation, and hemodialysis.[58] All fluoroquinolones are variably associated with this complication; however, pefloxacin and ofloxacin are more common culprits.[58],[59]

Drug-induced tendon injury generally occurs within 1–2 weeks, but time to development of an event may be varied rapidly within hours or may be overtly delayed for up to months or even after drug discontinuation. Fluoroquinolone-related tendon injuries have a predilection for the Achilles tendons (89%) and are afflicted bilaterally in almost half (44.3%).[58] Approximately 40% of patients experience tendon rupture.[60] Less commonly affected tendons were rotator cuff, extensor carpi radialis brevis, finger flexor tendons, and quadriceps tendon. Injuries generally affect the body of the tendon (especially Achilles tendon) rather than the enthesis.[53] Partial or complete tendon rupture occurs in almost half. Treatment consists of immediate withdrawal of the drug, rest and analgesics. Recovery is usual within 2 months, but chronic sequelae remain in up to 10%.[58]

Pathomechanisms are unclear. In a study of canine Achilles tendons maintained in ciprofloxacin concentrates, significant decreases in cell proliferation (66%–68%), collagen synthesis (36%–48%), and glycosaminoglycan synthesis (14%–60%) were noted after 72 h in, as was observed an increase in proteolytic activity in the extracellular matrix.[61] One hypothesis is generation of reactive oxygen species and subsequent mitochondrial functional aberration and induction of apoptosis of cellular elements and direct cytotoxic effect of these reactive oxygen species on extracellular matrix components.[62] Another hypothesis is increased generation of prostaglandin E2, interleukins, cyclooxygenase-2, and metalloproteinases.[63],[64]

The first reported case of corticosteroid-induced tendon rupture was more than five decades ago.[65] A 2005 systematic review reported that for oral corticosteroids, tendinopathy was associated with a median (interquartile range [IQR]) of 80 mg prednisolone equivalent (40–120), with a median (IQR) cumulative dose of 175 g (32–354), with a median latency period of 6 years (3 months to 30 years). Measures for the same for intra-articular steroids were 120 mg (30–240), 0.21 g (0.03–0.4), and 49 days (3 days to 6 years), respectively.[66] The authors also noted the afflicted cases were typically middle aged (mean age: 50 ± 17 years) and routes of administration were oral (33%) and intra-articular (35%) or parenteral (7%). Inhaled or topical steroid use was not entirely free of this adverse effect; however, the reports were isolated at best. Majority involved (93%) the Achilles tendon. Other afflicted tendons with >1% prevalence were patellar, biceps, tibialis anterior, calcaneus, peroneus brevis, extensor digitorum, flexor pollicis longus, quadriceps, and extensor pollicis longus in decreasing frequency. The rates of tendon rupture were 88% among Achilles tendon involvement and all others affected tendons presented as ruptures only. This may be linked to the fact that the Achilles is a large and sturdy tendon and withstands the insults for prolonged time before rupturing, and some patients may present with tendinopathy/tendinitis before rupturing. Others get ruptured before clinical notice. Only 37% of Achilles tendon involvement was bilateral, whereas 44% of patellar tendon and 50% of peroneus brevis and extensor digitorum tendon involvements were bilateral.

Other drugs less frequently implicated in tendonitis include statins, fibrates, and retinoids.[67] Poststatin exposure tendinopathy is a dose-independent class effect. The onset is around 8–10 months after initiation. Continued exposure has an incidence of 2% for tendinosis. The Achilles tendon is again the major cause of concern with just over 50% involvement. However, unlike fluoroquinolone tendinopathy, statin tendinopathy is unilateral in most cases with rupture rates ≤33%. Tendinopathy may recur with drug re-introduction.[60]

Recently, aromatase inhibitors were implicated in the occurrence of finger tenosynovitis. Some patients may mimic more classical presentations such as de Quervain's tenosynovitis or trigger finger. The incidence is up to 50%. About 20% of the affected may need treatment discontinuation. The presence of estrogen receptors within the pulleys and retinacula are thought to be explanatory.[68]

Five putative mechanisms explaining pathophysiology of drug-induced tendon disorders have been proposed.[53],[60],[69],[70] The first mechanism is aberrant tenocyte function. There are reduced production of collagen type I and increased production of collagen type III, which are less elastic. Diminished synthesis of glycosaminoglycans and heightened tenocyte apoptosis are also reported. Tenocyte apoptosis is postulated to result from generation of reactive oxygen species by neovascularization of normally avascular tendon body. Another mechanism of tenocyte apoptosis is glutamate-mediated excitotoxicity related to tendon degeneration. Second, altered intercellular signaling among tenocytes, especially amplified generation of proinflammatory cytokines (interleukins 1 and 6, cyclooxygenase-2, etc.), is hypothesized as one of the leading mechanisms of continued tendon damage. Third, owing to the previous two mechanisms, there is an increased activity of enzymes responsible for extracellular matrix degradation. Both fluoroquinolones and statins increase activity of matrix metalloproteinases, and glucocorticoids induce collagenase activity, resulting in higher rate of degradation of extracellular matrix. Fourth, drug-induced tendinopathy is linked to lipid dysregulation within tenocytes. Statins possibly modify cholesterol content of tenocyte plasma membranes. Moreover, the final mechanism is an aberrant and dysfunctional tendon repair process. This is especially important for glucocorticoid-related tendinopathy.


Both chronic hypervitaminosis A and long-term use of synthetic retinoids may result in diffuse idiopathic skeletal hyperostosis like disease.[71] Patients may be asymptomatic with only incidental radiological abnormalities or may complain of pain, stiffness, and decreased range of motion. Symptoms show poor correlation with radiographic findings. Radiological features include axial and/or peripheral ossifying enthesopathy with calcification of the anterior and posterior longitudinal vertebral ligaments. Isotretinoin causes more axial hyperostosis and acitretin is said to cause predominantly peripheral/appendicular calcification.[71],[72] The radiographic abnormalities are both dose-related and time-related.[2],[4],[72]

In one dermatology study,[73] 42 patients with acne vulgaris treated with isotretinoin (average dose: 30 mg/day; total dose: 120–150 mg/kg; duration: 4–6 months), the incidence of unilateral Achilles enthesopathy was seen in 3, and bilateral Achilles enthesopathy and unilateral sacroiliitis developed in 1 patient. Six patients on isotretinoin developed inflammatory back pain.

Periarticular calcifications

Periarticular calcifications are often seen several months after an intra-IACS injection, especially in the finger joints.[74] These are radiological peculiarities without any significant clinical stigmata. Most disappear with time.

Intradiscal corticosteroid therapy, in vogue with dubious evidence for the treatment of discogenic back pain or sciatica, may cause disc space degeneration and calcification.[75] While often asymptomatic, they may worsen back pain and nerve root compression.

Frozen shoulder

Frozen shoulder like syndrome has been described with the use of protease inhibitors used for the treatment of HIV infection,[76] fluoroquinolones,[77] isoniazid, and antiepileptic drugs, particularly barbiturates.[2],[78] Isoniazid and barbiturates are linked to the occurrence of a so-called shoulder-hand syndrome comprising complex regional pain syndrome of the hand and wrist with frozen shoulder.

Cyclosporine and tacrolimus have been linked to symmetrical epiphyseal pain syndrome and reflex sympathetic dystrophy of the lower limbs in transplant patients.[2],[79] High blood concentrations of these drugs are thought to result in this and lowering of doses and consequently lowering of blood levels result in disappearance of these symptomatologies.

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Conflicts of interest

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