Introduction

Health problems are self-reported by up to 64% of travellers to the developing world . Most of these problems are mild, self-limited illnesses such as diarrhoea, respiratory infections and skin disorders. However, up to 8% of the >50 million travellers to these regions are ill enough to seek health care either while abroad or on returning home. By contrast, rheumatic symptoms are often accorded little significance. For example, the largest contemporary experience in illness related to travel to developing countries comes from GeoSentinel, the global surveillance network of the International Society of Travel Medicine and the Centers for Disease Control and Prevention. In their 2006 report of 17,353 ill travellers from developing countries, data on rheumatological complaints were not recorded .

Many travellers return home with musculoskeletal symptoms with or without other accompanying complaints. The assessment of these patients is often hindered by the Western clinician’s lack of familiarity with the types of infections that the patient may have encountered while travelling. Furthermore, when presentation to health-care providers is delayed, the travel history may have been forgotten by the patient. A methodical approach to the evaluation of these patients is vital, and it should include basic information about the geographic distribution of infections in the locations where the person has lived and travelled (including even brief stays and airport transfers), as well as any activities that were undertaken. The evaluation of such patients should focus on determining what infections are possible given where the patient has lived or travelled, which of these infections is more probable given the patient’s clinical findings, pre-travel measures and potential exposures, as well as considering which of these infections is treatable or transmissible . These considerations also apply to recent immigrants from developing countries. Even in the absence of tropical infection, laboratory investigation of musculoskeletal symptoms in individuals of different ethnicities is challenging due to genetic and physiological variation. This review focusses on addressing the impact global migration has had on rheumatological clinical practice, with particular emphasis on the musculoskeletal manifestations of common tropical infections.

Alphaviruses

Alphaviruses that cause arthritis are globally distributed mosquito-borne RNA viruses causing epidemics of polyarthritis. Infections due to alphaviruses are increasingly being reported in travellers. Among all of the viruses that can cause arthritis, the alphaviruses are unusual, because nearly all symptomatic infections in adults result in joint symptoms. There are six groups: Ross River and Barmah Forest (Australia), Igbo-Ora (Africa), Sindbis virus group (Africa, Asia and Australia), Mayaro (South America), O’nyong–nyong (central and east Africa) and chikungunya (Caribbean, Asia, Africa, Western Pacific and Mediterranean regions) . Studies assessing the prevalence of travel-related rheumatic conditions are scarce, but in one series, the majority of returned travellers with musculoskeletal complaints presenting to a tropical medicine centre in Israel suffered with alphavirus infection . Chikungunya and Ross River virus (RRV) made up the majority of cases in this study.

Most alphavirus infections are associated with the triad of fever, rash and arthritis . Symptoms usually manifest after a 2–7-day incubation period, and their presentation can mimic a classical inflammatory arthropathy such as rheumatoid arthritis (RA) . This diagnostic confusion can be further exacerbated by the fact that some patients with alphavirus infection have low titre positive rheumatoid factor (RF) .

Alphaviruses

Alphaviruses that cause arthritis are globally distributed mosquito-borne RNA viruses causing epidemics of polyarthritis. Infections due to alphaviruses are increasingly being reported in travellers. Among all of the viruses that can cause arthritis, the alphaviruses are unusual, because nearly all symptomatic infections in adults result in joint symptoms. There are six groups: Ross River and Barmah Forest (Australia), Igbo-Ora (Africa), Sindbis virus group (Africa, Asia and Australia), Mayaro (South America), O’nyong–nyong (central and east Africa) and chikungunya (Caribbean, Asia, Africa, Western Pacific and Mediterranean regions) . Studies assessing the prevalence of travel-related rheumatic conditions are scarce, but in one series, the majority of returned travellers with musculoskeletal complaints presenting to a tropical medicine centre in Israel suffered with alphavirus infection . Chikungunya and Ross River virus (RRV) made up the majority of cases in this study.

Most alphavirus infections are associated with the triad of fever, rash and arthritis . Symptoms usually manifest after a 2–7-day incubation period, and their presentation can mimic a classical inflammatory arthropathy such as rheumatoid arthritis (RA) . This diagnostic confusion can be further exacerbated by the fact that some patients with alphavirus infection have low titre positive rheumatoid factor (RF) .

Chikungunya

Although found throughout the tropics, chikungunya is endemic to West Africa and it causes acute febrile polyarthralgia and arthritis. The name ‘chikungunya’ is derived from a local language of Tanzania meaning ‘that which bends up’. Serosurveys of communities in parts of West Africa have identified antibodies to chikungunya virus in 35–50% of the population . Multiple outbreaks beyond West Africa have been described. Since 2004 especially, chikungunya has spread broadly, causing massive outbreaks with explosive onset in the Indian Ocean region, India and other parts of Asia. Chikungunya had traditionally been perceived as a tropical disease until an outbreak in Italy in 2007 . In addition, thousands of cases have been identified in travellers returning from outbreak areas. It has received particular attention recently in the Western hemisphere due to an outbreak in 2014 in the Caribbean of >2000 confirmed cases and >7000 suspected cases .

Chikungunya is transmitted by mosquitoes of the Aedes species, especially Aedes aegypti and Aedes albopictus. In endemic areas of Africa, chikungunya virus transmission occurs in a cycle involving humans, several species of Aedes mosquitoes that inhabit forests and villages and animals (non-human primates and perhaps other animals). In Asia and elsewhere, however, major outbreaks are sustained by mosquito transmission among susceptible humans. The use of plastic containers in developing countries, where they are usually not correctly disposed and remain in the environment for years, has also been linked with the spread of the mosquitoes: acting as rainwater receptacles, and being exposed to sunlight, they can become perfect ‘incubators’ for mosquito eggs . Modes of mosquito dissemination internationally include transport of mosquito larvae and eggs in used tyres by container ships and air traffic with subsequent establishment in new areas with suitable environmental and climatic conditions. For example, the outbreak in Italy in 2007 was facilitated by a particularly warm summer that year, and some have postulated that climate change and global warming will be a significant factor in the future spread of chikungunya virus to new areas .

The incubation period of chikungunya ranges from 2 to 12 days . Many people infected with chikungunya will remain asymptomatic, and the disease is rarely fatal. The clinical presentation is very similar to that of dengue fever, the most common symptoms consisting of fever, arthralgia, backache and headache. Other symptoms include rash, fatigue, nausea, vomiting and myalgias . The joint symptoms of chikungunya are severe and often debilitating, lasting from weeks to up to a year, with the hands and feet most often affected, but the lower limbs and back can also be involved.

Persistent polyarthralgia and arthritis have been reported in 10–20% of patients infected with the chikungunya virus, lasting up to 36 months post infection in some series . Persistent chikungunya infection can mimic RA with some patients actually fulfilling the American College of Rheumatology (ACR) criteria for RA . Furthermore, bony erosions, effusions and marrow oedema on magnetic resonance imaging (MRI) have been demonstrated in individuals infected with chikungunya . A study on patients with chronic arthritic disability after chikungunya infection in Sri Lanka showed that the debilities persisted at the end of 3 years of follow-up in 6.1% of the patients , with associated health economic implications, especially in endemic areas. In another study of 88 patients in the Reunion Island who were evaluated a mean of 18 months after confirmation of acute chikungunya infection, 63% reported persistent polyarthralgia . Morning stiffness was reported by 75% of individuals, and almost half reported that the pain had a negative impact on daily activities. Factors associated with chronicity of symptoms included increasing age, and higher viral load and C-reactive protein (CRP) in the acute phase.

Other, less common but severe reported complications of chikungunya include Raynaud’s phenomenon, cryoglobulinaemia and muscle weakness .

Laboratory diagnosis of chikungunya can be achieved through virus culture, detection of viral RNA by polymerase chain reaction (PCR), presence of virus-specific immunoglobulin M (IgM) in the acute phase of the illness or fourfold increase in titres of immunoglobulin G (IgG) antibodies in samples taken 3 weeks apart . Serology is the principal tool for diagnosis in the clinical setting. IgM anti-chikungunya virus antibodies detected by direct enzyme-linked immunosorbent assay (ELISA) are present starting about 5 days (range 1–12 days) following onset of symptoms, and they persist for several weeks to 3 months. IgG antibodies begin to appear about 2 weeks following onset of symptoms and persist for years . If initial results are negative and chikungunya is still suspected, convalescent serum should be collected ≥7 days after illness onset and retested to detect IgM antibodies .

The case definition of chikungunya fever as proposed by the World Health Organization (WHO) Regional Office for Southeast Asia is outlined as follows .

As no specific drugs are available, supportive treatment for the symptoms, that is, analgesics, antipyretics and non-steroidal anti-inflammatory drugs (NSAIDs), is generally administered. A recent randomised, controlled study, comparing chloroquine with NSAIDs (meloxicam), failed to demonstrate any advantage of chloroquine over meloxicam . No antiviral agents have been shown to be effective in human infection, although ribavirin and interferon-alpha appear to have in vitro activity against virus replication . For critically ill patients, there are insufficient data for the use of corticosteroids or antiviral therapy and no licensed vaccine for the prevention of chikungunya infection.

Dengue

Dengue is the most prevalent mosquito-borne viral disease transmitted by mosquitoes of the genus Aedes . It is estimated that >390 million dengue virus infections occur each year throughout the world . Populations of approximately 112 tropical and subtropical countries worldwide are at a risk of dengue infection. The only continents that do not experience dengue transmission are Europe and Antarctica.

Classic dengue fever is marked by rapid onset of high fever, headache, retro-orbital pain, diffuse body pain (both muscle and bone), weakness, vomiting, sore throat, altered taste sensation and a centrifugal maculopapular rash . The haemorrhagic components of dengue are the most serious. Whereas most cases are relatively mild with petechiae, bleeding gums, epistaxis, menorrhagia and haematuria, some will develop life-threatening bleeds. Myalgias in dengue can be severe and especially affect the lower back, arms and legs. They can be accompanied by a raised creatine kinase level and they can progress to a frank myositis. Rhabdomyolysis has also been observed in patients with dengue . Arthralgias are frequently observed, and they are usually localised to the knees and shoulders. A peripheral polyarthralgia is often present, but it may be overshadowed by intense backache and pain in the long bones. Synovitis is uncommon . The severity of musculoskeletal pain in patients with dengue often requires the use of opiates. There have also been case reports suggesting that dengue can act as a trigger for immune-mediated vasculitis . Furthermore, acute dengue illness has been shown to mimic an acute lupus flare and also to trigger lupus flares with associated lupus nephritis .

Definitive laboratory diagnosis of dengue is obtained most commonly by demonstration of a fourfold or greater change in reciprocal IgG or IgM antibody titres to one or more dengue virus antigens in paired serum samples. Acute phase sample should be obtained ≥3 days after the onset of illness, and the IgM immunoassay (MAC-ELISA or equivalent) is the procedure of choice for rapid confirmation of the diagnosis.

Chikungunya and dengue virus infections have some common clinical symptoms and areas of geographic distribution; distinguishing them may be difficult in the setting of acute febrile illness with rash. However, symmetrical polyarthritis is far more common in chikungunya, with severe abdominal pain, vomiting, thrombocytopenia and bleeding more frequently seen in dengue . Both viruses can lead to a chronic disabling arthritis. Chikungunya is rarely fatal, whereas without proper case identification and management the fatality rate can be as high as 10% in patients with dengue . Therefore, patients suspected of having dengue or chikungunya should be managed as having dengue until dengue can be ruled out.

Those patients requiring hospitalisation should have their haemodynamic status maintained with judicious use of isotonic intravenous fluids. Pain and fever in patients with suspected dengue should be managed with paracetamol. If insufficient, opiates may be considered for pain management. NSAIDs should not be given initially to such patients because of the increased risk of bleeding manifestations if the patient has severe dengue . Once a suspected case has been afebrile for at least 48 h, with no warning signs of severe dengue, and continuing complaints of joint pain, NSAIDs may be considered. Physical therapy may also be beneficial.

Ross River virus

RRV is also transmitted by mosquitoes, and it causes a disease characterised by polyarthritis and rash. The illness was first described in northern Australia in 1928, and subsequently it has been observed widely throughout Australia and many islands of the western South Pacific. It is the most prevalent vector-borne disease in Australia. The virus can be transmitted by many mosquito species, and it survives in mosquito eggs in arid environments. Therefore, it has the capacity to spread to other geographic areas. The most striking clinical features of RRV infection are severe arthralgia and myalgia . Joint pains are present in >95% of patients. True arthritis occurs in 40% of patients. The joints of the extremities are most frequently involved, especially the wrists, knees, ankles and the metacarpophalangeal and interphalangeal joints of the fingers. Joint effusions and enthesopathy have also been reported. Other common symptoms include lethargy, fever, rash, headache and depression. In the acute setting, there is often significant functional impairment, with about half of patients requiring time off work. The role of RRV in chronic musculoskeletal symptoms is controversial. Early studies reported a significant minority of sufferers complaining of arthralgias, fatigue and depression for years after initial diagnosis. It has come to light more recently, however, that these initial studies did not control for pre-existing co-morbid conditions. Recent prospective studies have demonstrated that the vast majority of patients infected with RRV are symptom-free after 6 months .

Diagnosis is confirmed by serology. IgM is produced early in the course of infection, and hence its detection in an acute-phase sample, collected within 7 days of symptom onset, provides a presumptive diagnosis of recent infection. However, there is cross reactivity with other organisms (such as Barmah Forest virus) and false positives can be observed. Confirmation of the diagnosis therefore requires demonstration of IgG seroconversion . A convalescent sample should be collected 10–14 days later and tested in parallel by the same laboratory. Diagnosis is confirmed by a fourfold increase in IgG antibody titre. RRV can be detected by PCR; however, the usefulness of this test is doubtful, given that viraemia is typically short-lived.

No treatment has been shown to shorten the duration or alter the course of RRV. In most series, NSAIDs are reported to be the most effective treatment . Physiotherapy and hydrotherapy are also found to be beneficial for some. Steroids have also been used in a few cases, but their routine use is not currently recommended . The most important preventive measure is avoidance of mosquito bites with measures such as mosquito coils, repellents and light-coloured clothing.

Reactive arthritis

Reactive arthritis (ReA) is an aseptic inflammatory oligoarthritis triggered by gastrointestinal or genitourinary infections. When it presents with urethritis and conjunctivitis, it is known as Reiter’s syndrome. Gastroenteritis from Salmonella, Shigella , Campylobacter and Yersinia are well-documented triggers. Parenteral and oral typhoid vaccines have also been associated with ReA . In the aforementioned series of returned Israeli travellers with musculoskeletal symptoms, ReA was the second most common diagnosis . ReA typically occurs 1–4 weeks after the triggering infection. The oligoarthritis is asymmetric, and it predominantly involves the lower limbs or sacroiliac joint . Enthesopathy, especially at the heel, is common. Fever may be present at the onset of disease. Other common extra-articular manifestations include urethritis, conjunctivitis, anterior uveitis, oral ulcers, balanitis and various skin lesions. The erythrocyte sedimentation rate (ESR) and the CRP are frequently elevated, but they may be normal. The diagnosis of ReA is a clinical one, and there are no diagnostic laboratory tests. The mean duration of ReA symptoms is commonly up to 4–5 months; however, approximately 15–30% of patients will develop chronic disease, most having a positive family history for spondyloarthropathy or being positive for human leucocyte antigen (HLA)-B27 . NSAIDs are the mainstay of treatment. Intra-articular or oral steroids and steroid injections may be beneficial. Treatment of the triggering infection is warranted if the patient has persistent gastrointestinal symptoms at the time of diagnosis or if genitourinary infection with Chlamydia trachomatis was the trigger . Sulphasalazine, methotrexate and anti-tumour necrosis factor (TNF) biologic agents have been used in refractory cases .

As up to 55% of travellers to developing countries acquire traveller’s diarrhoea, and because complications such as ReA may develop weeks after the diarrhoeal episode, the association between ReA and traveller’s diarrhoea may be underappreciated. Consequently, it has been suggested that travellers at an increased risk of developing ReA (e.g., HLA-B27 positive or a history of spondyloarthropathy) should avoid high-risk eating behaviours. Some travel medicine physicians advocate the provision of antibiotic prophylaxis against traveller’s diarrhoea in some of these patients. Prophylaxis should target the pathogens most commonly associated with ReA. Fluoroquinolones are preferred unless the traveller will be in an area with a high prevalence of quinolone-resistant Campylobacter (e.g., Thailand), in which case azithromycin should be used .

HIV

Patients infected with HIV have been shown to have a higher risk of developing rheumatic diseases, and this can occur at any stage of the disease. Rheumatic conditions that have been described in association with HIV include HIV-associated arthropathy, seronegative spondyloarthropathies, connective tissue diseases, vasculitides, septic arthritis and pyomyositis. The HIV epidemic has changed the epidemiology of certain diseases (e.g., increased incidence of spondyloarthropathies and psoriatic arthritis), led to new disease due to the virus itself or therapy (e.g., HIV-associated arthropathy and antiretroviral-related myopathy), contributed as a new important aetiological factor (e.g., for vasculitides and osteonecrosis) and posed challenges to the management of common rheumatological conditions (e.g., RA and lupus). HIV-positive patients exhibit multiple antibodies on serologic evaluation, including anti-CCP, RF, antinuclear antibodies (ANAs), cryoglobulins, anticardiolipin antibodies, and anti-neutrophil cytoplasmic antibodies (ANCAs) . However, these are rarely of clinical significance, and once patients are started on antiretroviral therapy, these low-titre antibodies tend to resolve. Those patients with concomitant autoimmune disease (such as RA or lupus) and HIV experience remission of their rheumatological condition when CD4 counts are low. Once antiretroviral therapy is introduced, they can flare.

Monitoring of disease activity in patients with RA, systemic lupus erythematosus (SLE) or other rheumatological conditions who happen to be HIV positive can be problematic. For example, persistently raised ESR levels can be found in patients with HIV infection without active inflammatory arthritis. It has been observed that DAS-28 ESR overestimates disease activity by as much as 30% when compared to DAS28 CRP in individuals suffering from HIV infection and RA .

The potential issues with regard to disease-modifying antirheumatic drug (DMARD) therapy in HIV-positive patients are well documented, but controversial. However, methotrexate is now used cautiously in those with higher CD4 counts with close monitoring . Sulphasalazine , hydroxychloroquine , leflunomide and prednisolone have also been used in HIV-positive patients without deleterious effects on their HIV disease. Additionally, there are case reports of successful use of biological therapies (including infliximab, etanercept, adalimumab, rituximab and tocilizumab) in this group of patients .